sentence,pmcid,gene1,gene2,variant1,variant2,label
"Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"On the other hand, mutant GFP-@GENE$ A115P and @VARIANT$ showed perturbed interaction with HA-@GENE$. The residues @VARIANT$, I148, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103;tmVar:p|Allele|E|103;VariantGroup:2;CorrespondingGene:7010;RS#:572527340,0
"In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified @GENE$ variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, SRY, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants @VARIANT$ and @VARIANT$ activated the @GENE$ promoter similar to wt.",5893726,GATA4;1551,CYP17;73875,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"Our results indicate that the novel KCNH2-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas @GENE$-p.R583H, @GENE$-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNH2;201,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis.         We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: @VARIANT$, refSNP ID rs4935; Chr5: 179260213G/A, rs4797; Chr5: 179264731T/C, rs10277; Ch5: 179264915G/T, rs1065154 ].",5868303,TIA1;20692,SQSTM1;31202,c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,179260153C/T;tmVar:c|SUB|C|179260153|T;HGVS:c.179260153C>T;VariantGroup:9;CorrespondingGene:8878;RS#:4935;CA#:3600710,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (@VARIANT$; p.L16V) and @GENE$ (@VARIANT$).",3125325,USH1G;56113,USH2A;66151,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,1
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (@VARIANT$;p.R85C) inherited from an unaffected mother, and a @GENE$ (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.",5505202,WDR11;41229,EMX1;55799,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"Proband 17 inherited CHD7 @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).",8152424,DCC;21081,CCDC88C;18903,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"In Family F, the GJB2/@VARIANT$ was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the @VARIANT$/@GENE$, while the mother is heterozygous for the @GENE$/299-300delAT (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of TCF3 and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the @GENE$/TACI C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 T168fsX191 gene. Exons coding E2A functional domains, activation domain 1 and 2 (@GENE$, AD2) and helix-loop-helix (HLH) domains are shown.",5671988,TNFRSF13B;49320,AD1;56379,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The @VARIANT$ (p.His596Arg) mutation of @GENE$ has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). The c.317G>C (@VARIANT$) variant of @GENE$, a rare single nucleotide polymorphism (SNP, rs544478083), has not yet been shown to be related to PFBC and is likely benign predicted by Mutation Taster, PolyPhen-2, and PROVEAN (data not shown).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in GJB6. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and @GENE$ c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,CELSR1;7665,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), @GENE$: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).",7279190,FLNB;37480,TTC26;11786,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS2;12122,BBS6;10318,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"Moreover, patients carrying a LAMA4 @VARIANT$ mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in @GENE$ (@VARIANT$) and @GENE$ (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,MYH7;68044,MYBPC3;215,Pro943Leu;tmVar:p|SUB|P|943|L;HGVS:p.P943L;VariantGroup:5;CorrespondingGene:3910;RS#:387907365;CA#:143749,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB6;4936,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,DNAH17;72102,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0
It turned out to be that only @GENE$-c.3035C>T (@VARIANT$) and @GENE$-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.,5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; rs7673715) @VARIANT$; p.N409S and @GENE$ (MIM 600509; NM_000352.4; @VARIANT$) c.3989-9G>A mutations.,5505202,GBA;68040,ABCC8;68048,c.1226A>G;tmVar:c|SUB|A|1226|G;HGVS:c.1226A>G;VariantGroup:7;CorrespondingGene:2629;RS#:76763715;CA#:116767,rs151344623;tmVar:rs151344623;VariantGroup:4;CorrespondingGene:6833;RS#:151344623,1
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,VAPB;36163,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB p.M170I and @GENE$ p.R408C with SETX @VARIANT$ and @GENE$ p.T14I).,4293318,TAF15;131088,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Proband 17 inherited CHD7 @VARIANT$ and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant.",8152424,CDON;22996,FGFR1;69065,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
"In addition, we have confirmed that immunoreactive signal corresponding to the anti-ephrin-B2 antibody was colocalized with that to the anti-@GENE$ antibody in the inner ear (Supplementary Fig. 3g). These results suggest an important role of ephrin-B2 as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1.           Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of @GENE$ are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, @VARIANT$ were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, @VARIANT$ and F355L was not affected.",7067772,EphA2;20929,pendrin;20132,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"The most common mutation was p.R1110Q (@GENE$: c.3329G>A), which was found in 5 patients, accounting for 11% of all the cases. Of the 3 novel variants in DUOX2, @VARIANT$ was a frameshift mutation and had a potential deleterious effect on protein function and p.D137E and @VARIANT$ were missense mutations located in the peroxidase-like domain (Fig. S3A).  A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, DUOXA2 and TPO).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a @GENE$ mutation in association with mutation(s) in different genes.",7248516,DUOX2;9689,TPO;461,p.T803fs;tmVar:p|FS|T|803||;HGVS:p.T803fsX;VariantGroup:61;CorrespondingGene:50506,p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a).",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"These findings support the importance of @GENE$ as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in @GENE$ (@VARIANT$) and MYBPC3 (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYH7;68044,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ @VARIANT$ and @GENE$ p.R408C with SETX p.I2547T and SETX p.T14I).,4293318,VAPB;36163,TAF15;131088,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"(E) The @GENE$ mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in EDA and c.511C>T in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,LQT2;201,LQT6;71688,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"The mutations of KCNH2 p.307_308del and @GENE$ @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous SCN5A p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a). Except II: 1, other family members without cardiac event or cardiac disease did not carry KCNH2 mutation. Moreover, the conservation analyses demonstrated that the mutant sites of amino acid sequences of SCN5A and @GENE$ protein were highly conserved (Figure 2). Therefore, KCNH2 @VARIANT$ was considered as de novo mutation in II: 1 (Figure 1a and Figure 3).",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and PKD2 (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(Ser123Thr), and a second variant in @GENE$, p.(@VARIANT$).",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in @GENE$ (c.3925G > A, @VARIANT$) and a known DCM mutation in @GENE$ (c.2770G > A; @VARIANT$).",6359299,LAMA4;37604,MYH7;68044,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,1
"In Gata4ki mice with @VARIANT$ mutation interaction of Gata4 with cofactor Fog is abrogated, and consequently animals display anomalies of testis development. Moreover, GATA4 functionally interacts with NR5A1 in Sertoli cell cultures to positively regulate the expression of AMH, and therefore, it has been reported that mutations in NR5A1 may cause 46,XY DSD due to lack of interaction with @GENE$. No gonadal involvement is mostly detected in families with GATA4 mutations and isolated CHD, possibly because some of the variants retain some DNA-binding activity and exhibit different degrees of transcriptional activation on gonadal promoters and thus, remain able to synergize with NR5A1. In the present study, the @VARIANT$ mutation was found in a patient with a complex CHD, genital ambiguity, and persistent Mullerian ducts, which led to female gender assignment. We propose that cysteine to arginine change in position 238 of GATA4 lacks activity to bind DNA reducing the transactivation of @GENE$ critically.",5893726,GATA;6699,AMH;68060,p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463,p.Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (@VARIANT$) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,1
None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the @GENE$ [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; @VARIANT$] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).,6053831,PCDH15;23401,USH1G;56113,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,p.(Arg1034His);tmVar:p|SUB|R|1034|H;HGVS:p.R1034H;VariantGroup:2;CorrespondingGene:124590,0
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Her mother with @VARIANT$ in COL4A5 and her father with a missense mutation @VARIANT$ in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Molecular genetic studies A previously described homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*) had initially been identified in P1 and P2, for which their parents and unaffected sibling were heterozygous (Fig. 1). DNA was not available from the deceased sibling. The severity of the CH prompted investigation for an additional genetic mutation using whole-exome sequencing in P1 and P2. In addition to coding regions, significant intronic sequences were covered using this technique, enabling detection of a homozygous essential splice site change in @GENE$ (@VARIANT$), at the intron 14/exon 15 boundary, validated by Sanger sequencing in both cases.",5587079,DUOX2;9689,DUOX1;68136,c.1300C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,UNC13B;31376,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with @GENE$ p.M170I and TAF15 @VARIANT$ with SETX @VARIANT$ and SETX p.T14I).,4293318,ANG;74385,VAPB;36163,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (@VARIANT$), @GENE$ (rs143445685), @GENE$ (@VARIANT$), and DES (rs144901249) genes.",6180278,RYR1;68069,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"In patient AVM226, we identified the compound heterozygous variants c.3775G>A (@VARIANT$) and c.2966A>T (@VARIANT$) in @GENE$ (table 2). @GENE$ and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.",6161649,DSCAM;74393,DSCAML1;79549,p.Val1259Ile;tmVar:p|SUB|V|1259|I;HGVS:p.V1259I;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,p.Gln989Leu;tmVar:p|SUB|Q|989|L;HGVS:p.Q989L;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and @GENE$ mutations. KCNH2 p.307_308del and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus lead to a reduction of structural stability. However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d).",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, @VARIANT$ and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.3719G>A;tmVar:c|SUB|G|3719|A;HGVS:c.3719G>A;VariantGroup:87;CorrespondingGene:4647;RS#:542400234;CA#:5545997,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,CCNF;1335,ALS2;23264,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,VAPB;36163,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,ATP2A3;69131,VPS13C;41188,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"II: 1 carried the digenic heterozygous mutations of @GENE$ @VARIANT$ and @GENE$ p.R1865H. I: 1 and II: 2 were heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry KCNH2 mutation.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 @VARIANT$ and GFP-@GENE$ E229K to immunoprecipitate HA-TEK E103D and HA-@GENE$ @VARIANT$, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between @GENE$ and @GENE$ has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).",7549550,RIPPLY1;138181,MYOD1;7857,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"These two individuals were heterozygous carriers of @VARIANT$ mutation in @GENE$ and p.V255M in GGCX. Since heterozygous carriers of p.R1141X in ABCC6 alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance. In this case, haploinsufficiency of the carboxylase activity and reduced ABCC6 functions could be complementary or synergistic. The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the ABCC6 gene (p.R1141X) and the GGCX gene (p.S300F) yet did not display any cutaneous findings are not clear. Specifically, while both GGCX mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the @VARIANT$ mutation was more pronounced than that of p.V255M. In this context, it should be noted that the substrate employed in the carboxylase assay is a pentapeptide, Phe-Leu-Glu-Glu-Leu, and it is possible that the activity measurements if done on full-length @GENE$ as substrate would show differential activity with these two mutant enzymes.",2900916,ABCC6;55559,MGP;693,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS6;10318,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-TEK @VARIANT$, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant @GENE$ proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-@GENE$ @VARIANT$ and R368H showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Based on these findings, we conclude that, unlike LQTS-associated mutations, the @GENE$-@VARIANT$ variant does not severely affect the function of the channel. 2.3.2. @GENE$-p.C108Y Exhibits a Dominant-Negative Loss-of-Function Heterologous expression studies demonstrated that KCNH2-@VARIANT$ is a non-functional channel (Figure 4A).",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"This patient with the @VARIANT$ NELF missense mutation also had a hemizygous KAL1 deletion of the completely conserved @VARIANT$ within the whey-acidic-protein (WAP) domain that forms a disulphide bridge with Cys134 of anosmin-1 (Figure S1C,D). Unilateral renal agenesis in this patient is likely related to this deleterious KAL1 mutation. The third KS male was heterozygous for both @GENE$ and @GENE$ nonsense mutations.",3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,Cys163;tmVar:p|Allele|C|163;VariantGroup:9;CorrespondingGene:3730,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"  Functional characterisation of AIS-associated FLNB variants According to alignment to the @GENE$ protein domain, most of the AIS-associated FLNB variants are located within immunoglobulin-like filamin repeat regions, some of which belong to the domain of interaction with @GENE$ (figure 2A). Of note, @VARIANT$ is located within the actin-binding domain of FLNB. We transfected wild-type or mutant plasmids into HEK293T cells and found that some FLNB variants (including p.M1803L, p.S2503G and p.T2166M; online supplementary figure 1) resulted in cytoplasmic focal accumulation, and some other FLNB variants (including p.R566L, @VARIANT$, p.S2503G, p.R199Q and p.R2003H; online supplementary figure 2) altered actin dynamics (online supplementary figures 1 and 2).",7279190,FLNB;37480,FLNA;1119,p.R199Q;tmVar:p|SUB|R|199|Q;HGVS:p.R199Q;VariantGroup:0;CorrespondingGene:79989;RS#:1175244100,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and @GENE$ (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and @VARIANT$ (c.310T>C) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and @GENE$ p.T14I).",4293318,ANG;74385,SETX;41003,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0
"The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of WNT10A were detected. These mutations were not found in his father's genome, but because his mother's DNA sample was unavailable, the origin of the mutant alleles was not clear (Fig. 2F).     All novel mutations that were identified in this study were not found in the normal controls. Protein structure analysis The results of protein structure analyses of @GENE$ are shown in Figure 3.",3842385,EDA;1896,WNT10A;22525,p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-@VARIANT$, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
Future studies will focus on determining how double homozygous mutations in @GENE$ (@VARIANT$) and @GENE$ (@VARIANT$) result in increased intracellular pro-COL1A1 levels and increased pro-COLA1 secretion.,4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1
"(E) The EDA mutation @VARIANT$ and @GENE$ mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in @GENE$ and @VARIANT$ in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,WNT10A;22525,EDA;1896,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX @VARIANT$).",4293318,SOD1;392,TARDBP;7221,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The study revealed @GENE$ gene mutations in a majority of our cohort (33%), in accordance with the percentages already reported in the literature. Interestingly, we found just one patient with variants in BBS1, the most frequently detected gene in BBS patients. We identified a novel variant in BBS1 patient #10 c.1285dup (@VARIANT$) defined as pathogenic that segregates with phenotype together with c.46A > T (p.(Ser16Cys), defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, was identified in patient #3. BBS1, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of @GENE$ and BBS7 lie in this portion.",6567512,BBS10;49781,BBS2;12122,"p.(Arg429Profs*72);tmVar:p|FS|R,P|429|RO|72;HGVS:p.R,P429ROfsX72;VariantGroup:28;CorrespondingGene:582",p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,0
"Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,PRICKLE4;22752,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,CAPN11;21392,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"Co-segregation of TEK p.I148T and CYP1B1 @VARIANT$ was observed in two pedigrees and only a representative pedigree is shown. b Chromatograms of the four probands (lower panel) harboring the four different heterozygous @GENE$ mutations. The site of nucleotide change is indicated by an arrow, compared to the corresponding wild-type sequence (upper panel). c TEK protein sequence conservation across different species for the four mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A). The conserved residue for each mutation is highlighted in blue color. d Schematic representation of the TEK and CYP1B1 domains (Ig immunoglobulin, EGF epidermal growth factor, FN fibronectin, TM transmembrane, M membrane, H hinge region) indicating the location of the mutations identified in PCG (color figure online) TEK and @GENE$ interact in cells.",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"                                 CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ @VARIANT$ and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 @VARIANT$, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of @GENE$, p.R1044Q was within the third PDZ domain of SCRIB, @VARIANT$ located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,SCRIB;44228,CELSR1;7665,p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2). While @GENE$ blocks VEGF/VEGFR2 signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,RASA1;2168,TIMP3;36322,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"SCAP-c.3035C>T (p.Ala1012Val) variant impaired the negative feedback mechanism of cholesterol synthesize in H293T cell lines SCAP-c.3035C>T (@VARIANT$) variant was introduced into H293T cell lines by CRISPR-Cas9 methodology. After incubated with medium A (as described in the materials and methods section) for 6 hours, the wild-type goups showed a significant different distribution of SREBP-2 in cytoplasm and nucleus, (Figure 4A) while the @GENE$-mutated groups shows no such difference (Figure 4B). These phenomenon indicate that the mutated SCAP-c.3035C>T (p.Ala1012Val) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. AGXT2-c.1103C>T (p.Ala338Val) variant impaired the catabolism of ADMA in EA. hy926 cell lines @GENE$-@VARIANT$ (p.Ala338Val) variant was introduced into EA.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS7;12395,BBS6;10318,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS2;12122,BBS7;12395,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"Based on both clinical and laboratory quantification, it appears neither the @GENE$/TACI @VARIANT$ mutation nor the @GENE$ @VARIANT$ mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-@GENE$ @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished. GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%).",5953556,TEK;397,CYP1B1;68035,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
SCN5A @VARIANT$ and @GENE$ p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for @GENE$ and KCNH2 mutations. KCNH2 @VARIANT$ and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing.,8739608,KCNH2;201,SCN5A;22738,p.R1865;tmVar:p|Allele|R|1865;VariantGroup:1;CorrespondingGene:6331;RS#:370694515,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in MYD88 gene and a homozygous splice-donor mutation (@VARIANT$) in @GENE$ gene. (D) Western Blot of CARD9 and @GENE$ proteins performed on PBMC, EBVB, and PHA derived T cell lines.",6383679,CARD9;14150,MYD88;1849,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"Therefore, in this study, SCN5A p.R1865H may be the main cause of sinoatrial node dysfunction, whereas KCNH2 @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of @GENE$ p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and @GENE$ p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and @VARIANT$, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of NOD2 protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the @VARIANT$ substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,c.1051A > G;tmVar:c|SUB|A|1051|G;HGVS:c.1051A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
We identified a novel variant in the @GENE$ gene (c.2857A > G @VARIANT$) and two already described missense variants in the @GENE$ gene (S159G and @VARIANT$).,3975370,NOD2;11156,IL10RA;1196,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"@GENE$ and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2).",6161649,DSCAML1;79549,PTPN13;7909,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of @GENE$ were detected. These mutations were not found in his father's genome, but because his mother's DNA sample was unavailable, the origin of the mutant alleles was not clear (Fig. 2F).     All novel mutations that were identified in this study were not found in the normal controls. Protein structure analysis The results of protein structure analyses of WNT10A are shown in Figure 3. R171 and G213 are conserved residues through these organisms and located on conserved 2D fragments. Mutations of the residues could affect the function of the human WNT10A protein. In the case of R171C mutations, the substitution of Cys, a hydroxylic amino acid with a side chain shorter than Arg, might eliminate the electrostatic interaction of R171 with adjacent residues. The mutation G213S is expected to abolish the hydrophobic interaction of @VARIANT$ with adjacent residues.",3842385,EDA;1896,WNT10A;22525,p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216,0
"      WES revealed heterozygous mutations in two genes known to affect hypothalamic and pituitary development: @VARIANT$;p.R85C in @GENE$ (MIM 607123; NM_144773.2; rs141090506) inherited from an unaffected mother and c.1306A>G;@VARIANT$ in @GENE$ (MIM 606417; NM_018117.11; rs34602786) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1).",5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
"Hence, priority should be given to identifying the TCF3 @VARIANT$ mutation for preimplantation genetic diagnosis and/or chorionic villus sampling. Based on both clinical and laboratory quantification, it appears neither the @GENE$/TACI @VARIANT$ mutation nor the @GENE$ T168fsX191 mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The LRP6 @VARIANT$ mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,LRP6;1747,WNT10A;22525,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Because charged residues are important for proteins trafficking, the @VARIANT$ may result in accumulation of the Cx31 protein in intracellular compartments such as the Golgi apparatus or in other sites such as the endoplasmic reticulum or lysosomes. The A194T substitution might cause conformational changes within the Cx31 molecule or affect the ability of @GENE$ to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the Cx26 mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, R165W, F191L, and A197S in Cx26 as well as @VARIANT$, S198F and G199R in @GENE$, have been reported previously in patients with hearing impairment.",2737700,Cx31;7338,Cx32;137,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,F193C;tmVar:p|SUB|F|193|C;HGVS:p.F193C;VariantGroup:15;CorrespondingGene:2706,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  @GENE$, 23  @GENE$, 24  and CAPN9. 25  The RYR3 (NM_001036: @VARIANT$, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS.",7689793,EBNA1BP2;4969,TRIP6;37757,c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"This analysis indicated that the @GENE$ variant @VARIANT$ (rs138172448), which results in a p.Val555Ile change, and the @GENE$ gene variant c.656C>T (@VARIANT$), which results in a p.Thr219Ile change, are both predicted to be damaging.",6180278,CAPN3;52,DES;56469,c.1663G>A;tmVar:c|SUB|G|1663|A;HGVS:c.1663G>A;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"In our study, we identified four genetic variants in three genes (@GENE$-p.R583H, @GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$).",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"In our study, we identified four genetic variants in three genes (@GENE$-p.R583H, KCNH2-p.C108Y, @GENE$-@VARIANT$, and KCNE1-@VARIANT$).",5578023,KCNQ1;85014,KCNH2;201,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,1
"   Missense variants in the NEFH gene were detected in four patients: the T338I variant in two cases and the R148P and @VARIANT$ variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the E389Q and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene @GENE$ were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Subsequently many genes encoding folate pathway enzymes, transporters and receptors have been studied with mostly inconsistent findings.7 More recently, several candidate variants were identified in @GENE$ and @GENE$, 2 of the genes constituting the mitochondrial GCS.10, 32 In the present study, we identified a novel missense variant affecting the catalytic domain of the MTHFR gene. This patient additionally carried the @VARIANT$ variant, and a rare missense variant (@VARIANT$) in the GLDC gene.",5887939,AMT;409,GLDC;141,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332,0
"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and SCRIB @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, @GENE$ p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,PTK7;43672,CELSR1;7665,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and c.353A > G (@VARIANT$) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"@GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,DFNB1;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
We identified a novel variant in the @GENE$ gene (c.@VARIANT$ p.K953E) and two already described missense variants in the @GENE$ gene (@VARIANT$ and G351R).,3975370,NOD2;11156,IL10RA;1196,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,1
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"There is a splicing site mutation c.1339 + 3A>T in @GENE$, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"The patient carried a heterozygous variant of unknown significance in @GENE$, p.(@VARIANT$), defined as likely pathogenic in ClinVar, and a missense variant p.(@VARIANT$) in PMM2, classified as likely pathogenic. Recessive mutations in PMM2 were reported as associated to hyperinsulinemic hypoglycemia (HI) and @GENE$ (Cabezas et al.,).",7224062,PKHD1;16336,PKD;55680,His3124Tyr;tmVar:p|SUB|H|3124|Y;HGVS:p.H3124Y;VariantGroup:17;CorrespondingGene:5314,Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,TRPV4;11003,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,ENG;92,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD6;2617,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ @VARIANT$), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$).",5887939,PRICKLE4;22752,DVL3;20928,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"M2, @GENE$: p.(E387K). M3, CYP1B1: @VARIANT$. M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"        Ebermann et al. described a USH2 patient with ""digenic inheritance."" a heterozygous truncating mutation in GPR98, and a truncating heterozygous mutation in PDZ domain-containing 7 (@GENE$), which is reported to be a cause of USH. Our USH1 patient (Case #4) had segregated MYO7A:p.Ala771Ser and PCDH15:@VARIANT$. Molecular analyses in mouse models have shown many interactions among the USH1 proteins. In particular, MYO7A directly binds to PCDH15 and both proteins are expressed in an overlapping pattern in hair bundles in a mouse model. @GENE$:c.158-1G>A, predicted to alter the splice donor site of intron 3, has been classified as pathogenic. MYO7A:@VARIANT$ is a non-truncating mutation, but was previously reported as disease-causing.",3949687,PDZD7;129509,PCDH15;23401,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 @VARIANT$ and GFP-@GENE$ E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%).",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the @GENE$ protein (c.229C>T; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in @GENE$. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1
"The DUSP6 gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of @GENE$ were extracted, which revealed one common variant (c.-9 + 342A > G) in intron 1 with a MAF of 0.3 according to GnomAD.",8446458,SEMA7A;2678,PROKR2;16368,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"These results suggest an important role of ephrin-B2 as an inducer of @GENE$ endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1.           Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, @VARIANT$ and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by @GENE$ stimulation.",7067772,EphA2;20929,ephrin-B2;3019,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"A total of 2 novel variants, @VARIANT$ and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 @GENE$ variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and p.K618 were novel. p.C176R is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and p.R528S and p.K618* are located in the cytoplasmic loops (Fig. S3C). Patients with GIS had a higher tendency to be affected with mutations than patients with TD [25/32 (78%) vs. 6/11 (54%), Fig. 2]. Variants in TG, TSHR, @GENE$, SLC5A5 and PROP1 genes were found exclusively in patients with GIS, and 1 variant in TRHR was found in patients with TD.",7248516,TSHR;315,DUOXA2;57037,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The proband, who had @GENE$ p.(Asn1075Ser), p.(@VARIANT$), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the NRXN1 and NRXN2 proteins lead us to hypothesize that digenic variants in @GENE$ and @GENE$ contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"        Cardiac Phenotype: A @GENE$/NFATC1 Genetic Interaction The cardiac phenotype in the indexed-family is divided into two: a mild VSD not requiring any intervention and a severe TOF-like phenotype that required major intervention (Figure 1). We sought that differential variants inherited from the father would contribute to this differential expressivity of the ARS phenotype within the three affected children in this family: two with a cardiac phenotype and the third with only glaucoma. Interestingly, we unravel two novel missense mutations in @GENE$ (@VARIANT$) and NFATC1 (@VARIANT$) that are predicted to be damaging (Table 4).",5611365,FOXC1;20373,OBSCN;70869,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,0
"The proband's mother and aunt, also manifesting with PXE-like skin changes, were heterozygous carriers of a missense mutation (@VARIANT$) in @GENE$ and a null mutation (@VARIANT$) in the @GENE$ gene, suggesting digenic nature of their skin findings.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,1
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Moreover, mutations in residues close to @VARIANT$ and A194 identified in the families reported here, namely, M163L, R165W, F191L, and @VARIANT$ in Cx26 as well as F193C, S198F and G199R in Cx32, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the Cx31 gene except for the EC2 and TM4 domains, which are main domains for deafness mutations. This correlation between location of mutations and phenotypes, together with the identification of pathological mutations associated with hearing loss in the same region of the EC2 and TM4 domains in these three connexin genes (@GENE$, Cx31, and Cx32) suggested that the EC2 and TM4 domains are important to the function of the Cx31 protein in the inner ear and plays a vital role in forming connexons in the cells of the inner ear. In the present study, we have shown that the missense N166S and A194T mutations in @GENE$ acts in a recessive manner in three unrelated Chinese patients.",2737700,Cx26;2975,GJB3;7338,N166;tmVar:p|Allele|N|166;VariantGroup:0;CorrespondingGene:2707;RS#:121908851,A197S;tmVar:p|SUB|A|197|S;HGVS:p.A197S;VariantGroup:3;CorrespondingGene:2706;RS#:777236559,0
"DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. We found that mutations in the two genes segregated in the family and that the unaffected parents were healthy and carried heterozygous mutations in both SEC23A and @GENE$, consistent with an autosomal-recessive mode of inheritance. We also identified heterozygous mutation in @GENE$ in an unaffected sibling of tall stature and normal intelligence.",4853519,MAN1B1;5230,SEC23A;4642,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (@VARIANT$) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including @GENE$, @GENE$, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TPO;461,TG;2430,p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,ATP2A3;69131,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 @VARIANT$ and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A).",5887939,FZD;8321;8323,FAT4;14377,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,0
"Altogether, the results suggest that @GENE$ @VARIANT$ is a loss-of-function mutation in Drosophila. KAT2B F307S but not @GENE$ @VARIANT$ causes cardiac defects in Drosophila Since the presence of SRNS and heart defects in family A was the main phenotypic difference from the other families, we looked more specifically into the cardiac and renal system of the fly.",5973622,KAT2B;20834,ADD3;40893,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"The @VARIANT$ mutation would be predicted to generate a nonfunctional @GENE$ enzyme, and its digenic inheritance alongside the homozygous DUOX2 @VARIANT$ will likely result in complete absence of functional DUOX isoenzyme in our patients. It has been speculated that DUOX1 upregulation in the context of DUOX2 loss of function may at least partially compensate for defective H2O2 production. In support of this notion, the majority of reported biallelic @GENE$ mutations, which are known to truncate the protein before the H2O2-generating domains, cause transient or mild permanent CH, despite presumably abrogating DUOX2 activity completely (Table 1).",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,0
"                                 CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 @VARIANT$ and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of @GENE$ channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized.",8739608,SCN5A;22738,Kv11.1;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,KAL1;55445,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Moreover, patients carrying a @GENE$ @VARIANT$ mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and @GENE$ (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYBPC3;215,Pro943Leu;tmVar:p|SUB|P|943|L;HGVS:p.P943L;VariantGroup:5;CorrespondingGene:3910;RS#:387907365;CA#:143749,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,0
"One fetus with anencephaly (735F97) carried a rare missense mutation (c.2852C>A; @VARIANT$; rs147472391) in glycine decarboxylase (GLDC), which was previously reported as one of the causative mutated alleles in a compound heterozygous patient with the autosomal recessive disorder, non-ketotic hyperglycinemia (NKH, OMIM: 605899).30 @GENE$ encodes a component of the glycine cleavage system (GCS) in mitochondrial folate one-carbon metabolism, which has previously been implicated in both mouse and human NTDs.10, 11, 31, 32 Another individual with anencephaly (706F07) was heterozygous for a missense variant (c.200C>T; p.Thr67Ile; @VARIANT$) in the @GENE$ (CTH) gene, which causes cystathioninuria in a recessive form.33          Unreported and rare variants After filtering out intron, 3' and 5' UTR and synonymous variants, a total of 397 rare (MAF < 1%, including novel) variants were identified in 89/90 NTD cases from 110/191 of the panel of NTD candidate genes.",5887939,GLDC;141,cystathionine gamma-lyase;1432,p.Ser951Tyr;tmVar:p|SUB|S|951|Y;HGVS:p.S951Y;VariantGroup:20;CorrespondingGene:2731;RS#:147472391;CA#:4980035,rs28941785;tmVar:rs28941785;VariantGroup:30;CorrespondingGene:1491;RS#:28941785,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2).",6161649,ENG;92,BMP;55955,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0
"Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/@GENE$ @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,1
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for REEP4 c.109C>T. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of @VARIANT$ among vertebrates                @GENE$ missense variant A TOR2A nonsynonymous SNV (@VARIANT$ [NM_130459.3], p.Arg190Cys [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,BSP+;3644,TOR2A;25260,Arg37;tmVar:p|Allele|R|37;VariantGroup:10;CorrespondingGene:80346;RS#:780399718,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental CACNA1C-Q1916R mutation might be partly compensated by the persistent inward tail INa produced by the @GENE$-@VARIANT$ channel. That may be how SCN5A-R1193Q plays a protective role against the detrimental phenotype induced by the @GENE$-@VARIANT$ mutation.",5426766,SCN5A;22738,CACNA1C;55484,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"(A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,TRPV4;11003,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"C2orf74 gene might interact with @GENE$ gene product and give rise to the spectrum of phenotype varying from severe phenotype with complete penetrance to partial features. Conclusion In this study, we analysed a large family segregating Waardenburg syndrome type 2 to identify the underlying genetic defects. Whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach was performed and a novel single nucleotide deletion mutation (@VARIANT$) in the MITF gene and a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the @GENE$ was identified.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in MYO7A (p.K268R), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and @GENE$ were not found in 666 control alleles.",3125325,CDH23;11142,USH2A;66151,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"25  The RYR3 (NM_001036: c.7812C > G, @VARIANT$) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: @VARIANT$, p.Glu274Asp) and the @GENE$ (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25  The contribution of the genetic variants, other than @GENE$ and MUTYH, to cancer risk cannot be completely excluded.",7689793,CAPN9;38208,MSH6;149,p.Asn2604Lys;tmVar:p|SUB|N|2604|K;HGVS:p.N2604K;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"Neither the @VARIANT$ nor the @VARIANT$ variant has been reported as a mutation of a compound heterozygote in patients diagnosed with a myopathy secondary to mutations in either the DES or CAPN genes. Discussion The patient's history, clinical examination, EMG testing, muscle biopsy results, and the lack of response to any therapy suggest that he does not have an inflammatory myopathy but rather a genetic disorder. Mutations in CAPN3 and DES genes result in LGMD inherited in an autosomal recessive pattern. Homozygous or compound heterozygous mutations in the @GENE$ and DES genes cause LGMD 2A and @GENE$, respectively.",6180278,CAPN3;52,LGMD 2R;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Below symbols are indicated genotypes for @GENE$ and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, CYP1B1: @VARIANT$. M3, CYP1B1: p.(E173*). M4, PITX2: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases. +: wild-type allele. The asterisk indicates a de novo PITX2 variant. Evolutionary conservation of FOXC2 and @GENE$ variants Evolutionary amino acid or nucleotide sequence conservation analysis were assessed using a multiple sequence alignment of representative orthologous proteins or genes of seven different species, from fish to human.",6338360,CYP1B1;68035,PITX2;55454,p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"For example, @GENE$:@VARIANT$, which occurred in 0/384 control chromosomes and was predicted to be ""probably damaging"" by the Polyphen program, was found with a homozygous @GENE$ nonsense mutation (@VARIANT$) (Case #15).",3949687,USH1C;77476,CDH23;11142,p.Tyr813Asp;tmVar:p|SUB|Y|813|D;HGVS:p.Y813D;VariantGroup:3;CorrespondingGene:10083,p.Arg2107X;tmVar:p|SUB|R|2107|X;HGVS:p.R2107X;VariantGroup:4;CorrespondingGene:64072;RS#:773945008,1
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,CACNA1A;56383,GNA14;68386,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,0
  Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in @GENE$ (@VARIANT$) and a variant in @GENE$ (@VARIANT$).,5868303,SQSTM1;31202,TIA1;20692,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT5;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"Immunocomplex of myc-@GENE$ L117F, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after @GENE$ stimulation while EphA2 and other mutated pendrins were not affected.",7067772,pendrin;20132,ephrin-B2;3019,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"@GENE$E Molecular genetics of primary congenital glaucoma Digenic inheritance in medical genetics Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21 The trabecular meshwork outflow pathways: structural and functional aspects A lymphatic defect causes ocular hypertension and glaucoma in mice Role of CYP1B1 in glaucoma Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene Common and rare genetic risk factors for glaucoma Genetic interaction of TEK and CYP1B1 in PCG patients. a Pedigrees of four PCG families segregating the heterozygous TEK and CYP1B1 alleles. The affected probands are indicated by solid black symbols who harbor both the heterozygous mutant alleles, while their asymptomatic parents carry either of the corresponding heterozygous TEK or @GENE$ alleles. The genotypes of the individuals for the TEK and CYP1B1 mutations are indicated below the symbols. Asterisk indicates the siblings whose biological samples were unavailable. Co-segregation of TEK @VARIANT$ and CYP1B1 @VARIANT$ was observed in two pedigrees and only a representative pedigree is shown.",5953556,INPP5;8682,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and Cx31 have overlapping expression patterns in the cochlea.",2737700,GJB3;7338,Cx26;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) @GENE$:c.3329G>A (@VARIANT$) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"A single @GENE$ mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel @GENE$ missense variant @VARIANT$).",5887939,FZD1;20750,FAT4;14377,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"In patient AVM359, one heterozygous VUS (@VARIANT$ [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,ENG;92,VEGFR2;55639,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,0
Both sisters inherited the HNF4A gene mutation @VARIANT$ from their mother and the @GENE$ gene mutation P291fsinsC (@VARIANT$) from their father. The father was diagnosed with diabetes at 45 years of age. Their brother is heterozygous for the @GENE$ R127W mutation.,4090307,HNF1A;459,HNF4A;395,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,0
"Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (@GENE$)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in @GENE$ act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,DCC;21081,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"                                 CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. @GENE$ @VARIANT$ may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Moreover, patients carrying a @GENE$ Pro943Leu mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYBPC3;215,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"(b) The changed site of SCN5A gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant DISCUSSION In our study, the proband with overlapped phenotypes of young early-onset LQTS and sinoatrial node dysfunction was first demonstrated to carry with the digenic heterozygous and pathogenic mutations of @GENE$ @VARIANT$ and @GENE$ @VARIANT$. KCNH2 p.307_308del induced a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized, which thus mainly caused LQTS.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1
"Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation.       Variants in the @GENE$ gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2).",6707335,SIGMAR1;39965,KIF5A;55861,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Bioinformatic analysis predicted that @GENE$-G38S was ""tolerated"" and @GENE$-C108Y was ""damaging"", whereas divergent results were obtained for KCNQ1-R583H and KCNH2-K897T, i.e., some programs considered these variants ""damaging"" and others as ""benign"" (Table 2). Moreover, the MAF of KCNQ1-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and KCNE1-@VARIANT$ were much larger (0.187 and 0.352, respectively).",5578023,KCNE1;3753,KCNH2;201,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The affected probands are indicated by solid black symbols who harbor both the heterozygous mutant alleles, while their asymptomatic parents carry either of the corresponding heterozygous @GENE$ or CYP1B1 alleles. The genotypes of the individuals for the TEK and CYP1B1 mutations are indicated below the symbols. Asterisk indicates the siblings whose biological samples were unavailable. Co-segregation of TEK p.I148T and CYP1B1 @VARIANT$ was observed in two pedigrees and only a representative pedigree is shown. b Chromatograms of the four probands (lower panel) harboring the four different heterozygous TEK mutations. The site of nucleotide change is indicated by an arrow, compared to the corresponding wild-type sequence (upper panel). c TEK protein sequence conservation across different species for the four mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A). The conserved residue for each mutation is highlighted in blue color. d Schematic representation of the TEK and CYP1B1 domains (Ig immunoglobulin, EGF epidermal growth factor, FN fibronectin, TM transmembrane, M membrane, H hinge region) indicating the location of the mutations identified in PCG (color figure online) TEK and @GENE$ interact in cells.",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"We identified four genetic variants (KCNQ1-@VARIANT$, @GENE$-p.C108Y, KCNH2-p.K897T, and @GENE$-@VARIANT$) in an LQTS family.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, c.1070A > G (@VARIANT$) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis.         We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: 179260153C/T, refSNP ID rs4935; Chr5: @VARIANT$, rs4797; Chr5: 179264731T/C, rs10277; Ch5: 179264915G/T, rs1065154 ].",5868303,TIA1;20692,SQSTM1;31202,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,179260213G/A;tmVar:c|SUB|G|179260213|A;HGVS:c.179260213G>A;VariantGroup:0;CorrespondingGene:8878;RS#:4797;CA#:3600734,0
"Interestingly, we found just one patient with variants in @GENE$, the most frequently detected gene in BBS patients. We identified a novel variant in BBS1 patient #10 c.1285dup (p.(Arg429Profs*72)) defined as pathogenic that segregates with phenotype together with c.46A > T (@VARIANT$, defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, was identified in patient #3.",6567512,BBS1;11641,BBS7;12395,p.(Ser16Cys);tmVar:p|SUB|S|16|C;HGVS:p.S16C;VariantGroup:5;CorrespondingGene:582;RS#:772917364,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,0
"myc-pendrin A372V, @VARIANT$, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, @VARIANT$ and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of @GENE$ and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin S166N was not internalized after @GENE$ stimulation while EphA2 and other mutated pendrins were not affected.",7067772,EphA2;20929,ephrin-B2;3019,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 @VARIANT$ and SCRIB @VARIANT$).",5887939,CELSR1;7665,DVL3;20928,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ @VARIANT$, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"  Digenic inheritances of GJB2/@GENE$ and @GENE$/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,MITF;4892,GJB2;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"        Molecular Data All three probands carry two heterozygous variants: SQSTM1, c.1175C>T (p.Pro392Leu), and TIA1, @VARIANT$ (p.Asn357Ser). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and SQSTM1 variants have been reported in multiple databases. The @GENE$ variant is designated as @VARIANT$ in dbSNP and reported at allele frequencies of 0.0009 in the Exome Aggregation Consortium database (ExAC), 0.0024 in 1,000 Genomes Project database (TGP), and 0.0015 in the NHLBI GO Exome Sequencing Project (GO-ESP) (accessed January 23, 2018) and is more frequent in certain European populations.",5868303,TIA1;20692,SQSTM1;31202,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,rs104893941;tmVar:rs104893941;VariantGroup:1;CorrespondingGene:8878;RS#:104893941,0
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in @GENE$ to block its activity in @GENE$/TGF-beta signalling.",6161649,SMAD1;21196,BMP;55955,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 3;7338,gap junction protein beta 6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"We identified four genetic variants (KCNQ1-p.R583H, @GENE$-p.C108Y, KCNH2-p.K897T, and KCNE1-@VARIANT$) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, @GENE$-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-@VARIANT$, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type.",5578023,KCNH2;201,KCNQ1;85014,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"By contrast, the expression of human @GENE$ and @GENE$, either alone or in combination, did not restore the viability of the mutant (Fig 3C), suggesting that the human orthologs have evolved in structure and function in comparison to Gcn5. As the mutated amino acid in KAT2B, F307, is conserved in Drosophila Gcn5 (corresponding to Gcn5 F304), we re-expressed Gcn5 F304S in the Gcn5E333st hemizygous background (Gcn5 @VARIANT$). As a negative control, we re-expressed a predicted potentially damaging KAT2B variant (S502F corresponding to Gcn5 @VARIANT$) found in a homozygous state in a healthy individual from our in-house database.",5973622,KAT2A;41343,KAT2B;20834,F304S;tmVar:p|SUB|F|304|S;HGVS:p.F304S;VariantGroup:6;CorrespondingGene:39431,S478F;tmVar:p|SUB|S|478|F;HGVS:p.S478F;VariantGroup:13;CorrespondingGene:2648,0
"Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, @GENE$ c.28C > A (@VARIANT$) and @GENE$ c.742C > T (@VARIANT$).",7463850,GRIN2A;645,PLXNB2;66630,p.Leu10Met;tmVar:p|SUB|L|10|M;HGVS:p.L10M;VariantGroup:0;CorrespondingGene:2903,p.Arg248Cys;tmVar:p|SUB|R|248|C;HGVS:p.R248C;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0
"Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,SPTBN4;11879,MYOD1;7857,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Three variants in three genes were rare, including the @GENE$ gene mutation [p.(Lys205del)], a novel heterozygous missense variant [@VARIANT$; p.(@VARIANT$)] in the SEMA7A gene (NM_001146029), as well as a splice site variation in the @GENE$ gene (NM_032242; MAF = 0.03 in GnomAD).",8446458,PROKR2;16368,PLXNA1;56426,c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and @GENE$ (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS.",7689793,EBNA1BP2;4969,TRIP6;37757,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"The proband is heterozygous for the @GENE$/TACI @VARIANT$ mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (@VARIANT$) in the @GENE$ (TCF3) gene encoding the E2A transcription factors, present only in the proband and her son.",5671988,TNFRSF13B;49320,Transcription Factor 3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, @VARIANT$) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous SCN5A @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,LAMA2;37306,KCNH2;201,c.A3083T;tmVar:c|SUB|A|3083|T;HGVS:c.3083A>T;VariantGroup:5;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, @VARIANT$) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,p.Met1445Val;tmVar:p|SUB|M|1445|V;HGVS:p.M1445V;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
   Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the GCK gene and in exon 4 (@VARIANT$; p.Pro291Arg) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B).,8306687,GCK;55440,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1
"We identified four genetic variants (KCNQ1-p.R583H, KCNH2-@VARIANT$, @GENE$-p.K897T, and @GENE$-@VARIANT$) in an LQTS family.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and @GENE$ (c.9921T>G).",3125325,CDH23;11142,USH2A;66151,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0
"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We transfected wild-type or mutant plasmids into HEK293T cells and found that some FLNB variants (including p.M1803L, p.S2503G and p.T2166M; online supplementary figure 1) resulted in cytoplasmic focal accumulation, and some other FLNB variants (including p.R566L, p.A2282T, p.S2503G, @VARIANT$ and @VARIANT$; online supplementary figure 2) altered actin dynamics (online supplementary figures 1 and 2).  @GENE$ and @GENE$ variants in individuals with AIS. (A) Profiles of rare damaging variants in FLNB.",7279190,FLNB;37480,TTC26;11786,p.R199Q;tmVar:p|SUB|R|199|Q;HGVS:p.R199Q;VariantGroup:0;CorrespondingGene:79989;RS#:1175244100,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS6;10318,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,VAPB;36163,ANG;74385,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (@GENE$) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,OPTN;11085,TBK1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,1
"Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of @GENE$ function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"Given the reported normal function of pendrin @VARIANT$ and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,EphA2;20929,ephrin-B2;3019,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB c.3323G > A (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. Location analysis of missense changes showed that @VARIANT$ was located very close to the fourth PDZ domain (1109-1192) of @GENE$. The PDZ domains of human SCRIB are required for correct localization and physical interaction with other proteins, such as the core PCP protein VANGL2, which is required for transducing PCP signals.",5966321,CELSR1;7665,SCRIB;44228,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, @VARIANT$, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,c.379T>A;tmVar:c|SUB|T|379|A;HGVS:c.379T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely @VARIANT$, p.P79T, p.S82T, p. A85P, @VARIANT$, p.F112S, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.Q70Hfs*8;tmVar:p|FS|Q|70|H|8;HGVS:p.Q70HfsX8;VariantGroup:8;CorrespondingGene:6012,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"These seven amino acids are located in the peroxidase- (PO-) like domain and are conserved among @GENE$ orthologs (Figure 2 and Figure S1). The latter variant likely resulted in aberrant splicing of the transcript. Two novel variants were identified in TG, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (c.1514G>A, @VARIANT$). A novel missense mutation was found in @GENE$ (c.398G>A, @VARIANT$).",6098846,DUOX2;9689,DUOXA2;57037,p.G505D;tmVar:p|SUB|G|505|D;HGVS:p.G505D;VariantGroup:10;CorrespondingGene:7173;RS#:867829370,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Six variants in @GENE$ occurred de-novo, three of which were not previously described: c.3236del p.(Asp1079Alafs*25), @VARIANT$ p.(Glu2954*), and c.9201+1G>A. One de-novo and novel variant was also detected in @GENE$: c.992G>A p.(@VARIANT$).",7224062,PKD1;250,PKD2;20104,c.8860G>T;tmVar:c|SUB|G|8860|T;HGVS:c.8860G>T;VariantGroup:46;CorrespondingGene:5310,Cys331Tyr;tmVar:p|SUB|C|331|Y;HGVS:p.C331Y;VariantGroup:1;CorrespondingGene:23193;RS#:144118755,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (p.R559W) and PKHD1: c.7942G > A (@VARIANT$), which were inherited from the mother and the father, respectively (Figure 3).          Whole-exome sequencing revealed that the foetal PKD proband in Family 23 had compound heterozygous variants in @GENE$, which was subsequently verified through Sanger sequencing.",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,p.G2648S;tmVar:p|SUB|G|2648|S;HGVS:p.G2648S;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the 497A>G (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the @VARIANT$ (A194T) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of Cx31 and @GENE$ in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against Cx26 (a) and @GENE$ (b).,2737700,Cx26;2975,Cx31;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,580G>A;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in @GENE$, @VARIANT$ and a previously identified mutation in @GENE$, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1
"c.223 - 4C > A might affect the normal splicing of exons in the PROK2 gene, and the novel variant @VARIANT$ (p. Arg102Ser) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a PROK2 gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the @GENE$ gene were found in eight patients. c.337 T > C (p. Tyr113His) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. c.491G > A (p. Arg164Gln) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors. The hot spot variant @VARIANT$ (p. Trp178Ser) was found in six patients and located in the transmembrane domain of the protein, which could significantly reduce the release of ionized calcium and the signal activity.                             The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the FGF/@GENE$ signalling pathway.",8796337,PROKR2;16368,FGFR1;69065,c.306G > C;tmVar:c|SUB|G|306|C;HGVS:c.306G>C;VariantGroup:27;CorrespondingGene:60675,c.533G > C;tmVar:c|SUB|G|533|C;HGVS:c.533G>C;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917,0
"Myopathy With @GENE$ and @GENE$ Variants: Clinical and Pathological Features Objective The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Patients and methods Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, @VARIANT$) and a heterozygous variant in TIA1 (c.1070A>G, @VARIANT$).",5868303,SQSTM1;31202,TIA1;20692,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants @VARIANT$; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,DVL3;20928,FZD6;2617,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in @GENE$ (DCC)p. Gln91Arg, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant p. Val969Ile of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. CDON seems to act similarly as @GENE$ through a digenic/oligogenic model to contribute to IHH. Case P06 had a missense variant in GADL1 (@VARIANT$), predicted as probably damaging.",8152424,DCC netrin 1 receptor;21081,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Ser221Cys;tmVar:p|SUB|S|221|C;HGVS:p.S221C;VariantGroup:5;CorrespondingGene:339896;RS#:775162663;CA#:2294666,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (c.229C>T; @VARIANT$) and d) the c.238-241delATTG (@VARIANT$) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,CELSR1;7665,PTK7;43672,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
The @GENE$-@VARIANT$ variant was previously reported to be associated with LQTS; KCNH2-p.C108Y is a novel variant; and @GENE$-p.K897T and KCNE1-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels.,5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.@VARIANT$ p. S159G) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature.",3975370,NOD2;11156,IL10RA;1196,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,0
Protein structure analysis We performed protein structure analysis on the two @GENE$ mutations (@VARIANT$ and p.G213S) and two novel @GENE$ mutations (@VARIANT$ and p.I312M) that were identified in this study.,3842385,WNT10A;22525,EDA;1896,p.R171C;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).    DISCUSSION In this study, we performed exome sequencing on 584 patients with @GENE$ and without a molecular diagnosis.",7549550,RIPPLY1;138181,CS;56073,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"Detection of mutations in @GENE$ and @GENE$ in group I are relatively common in East Asian populations, including Koreans, indicating that application of panel sequencing covering the genes prioritized based on the ethnicity-specific prevalence would be effective for identifying GJB2 single heterozygotes with severe to profound SNHL in Koreans. For the family SH60 with a most likely genetic etiology but without a clear result after TES, whole exome sequencing can be used for definitive molecular diagnosis. This family SH60 segregates prelingual or perilingual severe to profound SNHL, likely in an autosomal dominant fashion, although prelingual SNHL of SH60-136 was caused by autosomal recessive mutations in other deafness genes (Figure 3). Further segregation analyses of the two variants (p.R143W and p.D771N) among the six family members of SH60 as well as clinical evaluations including audiograms excluded both @VARIANT$ of GJB2 and @VARIANT$ of WFS1 as a molecular etiology of SH60-136.",4998745,MYO15A;56504,TMC1;23670,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Representative western blot and bar graph showing expression levels of SEC23A (A) and @GENE$ (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23A@VARIANT$/M400I MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001.",4853519,MAN1B1;5230,GAPDH;107053,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"@GENE$ and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (@VARIANT$) were identified in PTPN13 (table 2).",6161649,DSCAML1;79549,DSCAM;74393,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"(c, d) @GENE$ @VARIANT$ showed no significant influence on the RNA structure, and the MFE value of SCN5A p.R1865H mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), @GENE$ @VARIANT$ showed a decreasing trend in molecular weight and increasing instability.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2). While @GENE$ blocks VEGF/VEGFR2 signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,RASA1;2168,TIMP3;36322,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of @GENE$ to respond to ligand stimulation, indicating perturbed TEK signaling.",5953556,CYP1B1;68035,TEK;397,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and KCNQ1-c.G1748A (@VARIANT$) were introduced into @GENE$ and @GENE$ cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,1
"However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) @VARIANT$, and the rest were missense variants. However, the possibility of being loss-of-function intolerant (pLI) value of @GENE$ is zero, which means that single heterozygous LoF variant of IGSF10 is not sufficient to cause disease.",8152424,CCDC88C;18903,IGSF10;18712,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,0
"Interestingly, they found no disease-related or sudden death in this family, whereas disease-related deaths and sudden deaths were much more common in families carrying the @GENE$ @VARIANT$ variant. The p.E924K variant may, therefore, produce a more subtle phenotype. Morner et al. reported a case in a Swedish patient digenic for MYH7 p.E924K and @GENE$ @VARIANT$ mutations, the carriers of the MYBPC3 variant apparently having late-onset HCM.",6359299,MYH7;68044,MYBPC3;215,Arg403Gln;tmVar:p|SUB|R|403|Q;HGVS:p.R403Q;VariantGroup:3;CorrespondingGene:4625;RS#:121913624;CA#:10365,Val896Met;tmVar:p|SUB|V|896|M;HGVS:p.V896M;VariantGroup:7;CorrespondingGene:4607;RS#:35078470;CA#:12837,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ @VARIANT$, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,PTK7;43672,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, @VARIANT$, p. A85P, p.L86F, p.F112S, @VARIANT$, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.S82T;tmVar:p|SUB|S|82|T;HGVS:p.S82T;VariantGroup:111;CorrespondingGene:6012,p.R127L;tmVar:p|SUB|R|127|L;HGVS:p.R127L;VariantGroup:19;CorrespondingGene:2296;RS#:1085307884,0
"His cells produced higher levels of IgG and IgM than his mother (II.2, who bears both the TNFRSF13B/TACI @VARIANT$ and TCF3 @VARIANT$ mutations).    The combination of @GENE$ T168fsX191and @GENE$/TACI C104R mutations in the proband resulted in a greater net effect that the sum of each individual mutation would predict than the sum of deficits observed for each mutation alone (that is, Ig levelIII.2-(IgIII.2-IgIII.1)+(IgIII.2-IgII.3)).",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, @GENE$ and @GENE$).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B).",7248516,DUOXA2;57037,TPO;461,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,0
"While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-@GENE$ A372V, L445W, @VARIANT$, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,pendrin;20132,EphA2;20929,Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB6;4936,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,1
"These two individuals were heterozygous carriers of @VARIANT$ mutation in ABCC6 and @VARIANT$ in GGCX. Since heterozygous carriers of p.R1141X in @GENE$ alone do not manifest PXE and @GENE$ mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,1
"Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23.",3125325,MYO7A;219,CDH23;11142,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,0
"Sequence alterations were detected in the COL6A3 (rs144651558), RYR1 (@VARIANT$), CAPN3 (rs138172448), and DES (@VARIANT$) genes. These variants were then screened in his sister who had inherited all variants except that found in the @GENE$ gene. The @GENE$ and RYR1 variants were predicted to be benign by SIFT and PolyPhen and MutationTaster analysis.",6180278,CAPN3;52,COL6A3;37917,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"The large genomic rearrangement in @GENE$ previously reported by Le Guedard et al. was not detected in this group of patients. Three pathogenic or presumably pathogenic mutations in @GENE$ were found in three patients, specifically, an already reported nonsense mutation (p.W38X), a novel nucleotide duplication (c.84dupC; @VARIANT$), and a novel sequence variant (c.46C>G; @VARIANT$).",3125325,PCDH15;23401,USH1G;56113,p.D29fsX29;tmVar:p|FS|D|29||29;HGVS:p.D29fsX29;VariantGroup:279;CorrespondingGene:26839,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The p.Ile312Met (@VARIANT$) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"    Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"These results suggest an important role of ephrin-B2 as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of @GENE$.           Aberrant regulation of pathogenic forms of @GENE$ via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected.",7067772,ephrin-A1;3262,pendrin;20132,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,1
"One heterozygous NELF splice mutation (@VARIANT$) has been described. However, the only KS individual within the family also had a heterozygous @GENE$ mutation (@VARIANT$), suggesting digenic disease. This @GENE$ deletion was associated with exon 10 skipping, but was not sufficient to cause KS alone.",3888818,FGFR1;69065,NELF;10648,c.1159-14_22del;tmVar:c|DEL|1159-14_22|;HGVS:c.1159-14_22del;VariantGroup:12;CorrespondingGene:26012,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin @VARIANT$, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
"Circles, female; squares, male; gray, @GENE$/TACI C104R mutation; blue TCF3 T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the TNFRSF13B/TACI C104R mutation.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ @GENE$ proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ FLNB proteins, respectively (figure 2D, E).",7279190,FLNB;37480,TTC26;11786,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"    Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. (C) The @GENE$ mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant EDA allele from his mother; WNT10A mutations in the parents could not be analyzed. (D) The EDA mutation @VARIANT$ and WNT10A mutation c.637G>A were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis.",3842385,WNT10A;22525,EDA;1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,MYOD1;7857,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, @VARIANT$; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,1
"p.R1110Q was the most common mutation identified in our patient cohort, which differed from previous reports in Korean (p.G488R) and Japanese (@VARIANT$) populations. Additionally, p.K530X was the most common mutation identified in Chinese patients from southern or central China. Besides DUOX2, TG anomalies are another common cause of DH. However, in the present study, four detected @GENE$ variants presented separately in four different patients with heterozygosity and always cooccurred with variants in DUOX2 or other DH-related genes, indicating that the contributions of TG mutations to DH in Xinjiang Han Chinese might be less important. More CH-associated @GENE$ mutations were found recently. Our study identified two known truncating variants, p.Y246X and @VARIANT$, which cooccurred in a patient with permanent CH.",6098846,TG;2430,DUOXA2;57037,p.R855Q;tmVar:p|SUB|R|855|Q;HGVS:p.R855Q;VariantGroup:45;CorrespondingGene:50506,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK @VARIANT$ (~70%). No significant change was observed with HA-@GENE$ G743A with GFP-@GENE$ @VARIANT$ as compared to WT proteins (Fig. 2).,5953556,TEK;397,CYP1B1;68035,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"A rare variant in @GENE$, c.428C>T; @VARIANT$, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported @GENE$/FOG2 (c.1632G>A; @VARIANT$) pathogenic missense alteration was identified.",7696449,AMH;68060,ZFPM2;8008,p.Thr143Ile;tmVar:p|SUB|T|143|I;HGVS:p.T143I;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,p.Met544Ile;tmVar:p|SUB|M|544|I;HGVS:p.M544I;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"In our study, we identified four genetic variants in three genes (@GENE$-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and @GENE$-@VARIANT$).",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
The mutations of @GENE$ @VARIANT$ and @GENE$ @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We identified four genetic variants (@GENE$-p.R583H, KCNH2-p.C108Y, @GENE$-p.K897T, and KCNE1-@VARIANT$) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-@VARIANT$, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type.",5578023,KCNQ1;85014,KCNH2;201,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, @GENE$, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in @GENE$ (WFS1) (NM_001145853) according to TES.",4998745,DFNB3;56504,Wolfram syndrome 1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (@VARIANT$) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling.",6161649,MAP4K4;7442,BMP;55955,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"  Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (@VARIANT$); P1, P2: thyrotropin >100 microU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (@VARIANT$) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred. Conclusion: This is a report of digenic mutations in DUOX1 and DUOX2 in association with CH, and we hypothesize that the inability of @GENE$ to compensate for @GENE$ deficiency in this kindred may underlie the severe CH phenotype.",5587079,DUOX1;68136,DUOX2;9689,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach was performed and a novel single nucleotide deletion mutation (@VARIANT$) in the @GENE$ gene and a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the @GENE$ was identified.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,1
"A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different @GENE$ mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,TIA1;20692,SQSTM1;31202,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-@GENE$ @VARIANT$ with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2).,5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ @VARIANT$, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,PTK7;43672,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,UBQLN2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Sequence alterations were detected in the COL6A3 (rs144651558), RYR1 (@VARIANT$), CAPN3 (rs138172448), and DES (@VARIANT$) genes. These variants were then screened in his sister who had inherited all variants except that found in the CAPN3 gene. The @GENE$ and RYR1 variants were predicted to be benign by SIFT and PolyPhen and MutationTaster analysis. The @GENE$ variant c.1663G>A (rs138172448) results in a p.Val555Ile change.",6180278,COL6A3;37917,CAPN3;52,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 T168fsX191 and @GENE$/TACI C104R mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and @GENE$ @VARIANT$), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD;8321;8323,CELSR2;1078,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"These mutations are expected to affect the three classes of @GENE$ isoforms (Tables 2, 3, Figure 1). Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A), a novel nucleotide deletion (c.6404_6405delAG; @VARIANT$), and six missense mutations, four of which (p.R1189W, p.R1379P, @VARIANT$, and p.R3043W) had not been previously reported.",3125325,harmonin;77476,CDH23;11142,p.E2135fsX31;tmVar:p|FS|E|2135||31;HGVS:p.E2135fsX31;VariantGroup:3;CorrespondingGene:64072;RS#:55947063,p.D2639G;tmVar:p|SUB|D|2639|G;HGVS:p.D2639G;VariantGroup:219;CorrespondingGene:65217,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT6;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS2;12122,BBS6;10318,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"@VARIANT$ lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this G-protein coupled receptor, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in CHD7, @GENE$, FGFR1, PROK2, PROKR2, TAC3, KAL1, GNRHR, @GENE$, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (@VARIANT$) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;p.Thr478Ala from NP_056352).",3888818,FGF8;7715,GNRH1;641,Trp275;tmVar:p|Allele|W|275;VariantGroup:1;CorrespondingGene:6870;RS#:144292455,p.Thr480Ala;tmVar:p|SUB|T|480|A;HGVS:p.T480A;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,0
"Genotype + and - indicate in the figure wild type and mutated, respectively. (B) Percentage of CD3+CD4+@GENE$+ cells after PMA stimulation (mean +- SEM of n = 2). (C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in @GENE$ gene and a homozygous splice-donor mutation (@VARIANT$) in CARD9 gene.",6383679,IL17;1651,MYD88;1849,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. Location analysis of missense changes showed that p.G1108E was located very close to the fourth PDZ domain (1109-1192) of @GENE$. The PDZ domains of human SCRIB are required for correct localization and physical interaction with other proteins, such as the core PCP protein VANGL2, which is required for transducing PCP signals.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The @GENE$ @VARIANT$ mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"All exons including the 5' and 3' untranslated regions of the @GENE$, @GENE$, SCN5A, KCNE1, and KCNE2 genes were amplified by polymerase chain reaction (PCR). The PCR products were screened for mutations by direct sequencing (Applied Biosystems Big-Dye Terminator v1.1 cycle sequencing kit; Life Technologies, Grand Island, NY, USA) with an Applied Biosystems Prism 3100 DNA Analyzer (Life Technologies, Grand Island, NY, USA) using previously reported protocols. In silico predictions of pathogenicity were made using the Alamut  Visual software (Interactive Biosoftware, Rouen, France), and population allele frequencies were determined using the ExAC Browser (Beta) database.      4.3. Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and KCNQ1-@VARIANT$ (p.R583H) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously.",5578023,KCNQ1;85014,KCNH2;201,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and @GENE$ (c.9921T>G).",3125325,MYO7A;219,USH2A;66151,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"All six affected family members, and none of the three unaffected persons, had a heterozygous @GENE$ @VARIANT$/p.Asn197Ilefs*81 mutation as well as a heterozygous @GENE$ c.1559G>A/@VARIANT$ mutation.",6785452,ENAM;9698,LAMA3;18279,c.588 +1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,1
"Her fasting C-peptide was 0.86 ng/mL (reference range: 0.5-3 ng/dL) and 60-minute stimulated C-peptide was 1.96 ng/mL. Due to the negative diabetes autoantibody panel, she underwent genetic testing as part of the SEARCH monogenic diabetes ancillary study at 11 years of age demonstrating a heterozygous missense mutation in exon 4 of HNF4A, R127W (@VARIANT$) and a heterozygous frameshift mutation in exon 4 of @GENE$, P291fsinsC (@VARIANT$). @GENE$ therapy was completely discontinued and she was started on glipizide (1.25 mg once daily) with the dose titrated to 2.5 mg once daily based on blood sugar checks, with weekly blood sugar reviews and close support from a diabetes specialist nurse practitioner.",4090307,HNF1A;459,Insulin;173,c.379C>T;tmVar:c|SUB|C|379|T;HGVS:c.379C>T;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,0
"Under these conditions, co-expression of @GENE$ did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, @VARIANT$ or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Most intriguingly, the more severely affected of the two patients, Patient 3, was found to harbor a known heterozygous variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), a testes determining gene associated with heart anomalies, and this variant has been previously reported in an individual with diaphragmatic hernia (Bleyl et al., 2007). We postulate that the cumulative effect of these changes in two different genes may be contributing to the patient's more severe phenotype.           In a second example, we identified a monoallelic change in SRD5A2 (c.G680A, p.Arg227Gln, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of SRD5A2, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014).",5765430,ZFPM2;8008,SF1;138518,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in @GENE$ (@VARIANT$; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.",7877624,EDNRB;89,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in @GENE$ to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,SMAD1;21196,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (@VARIANT$; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"We identified four genetic variants (@GENE$-@VARIANT$, KCNH2-p.C108Y, @GENE$-p.K897T, and KCNE1-@VARIANT$) in an LQTS family.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"          In a second example, we identified a monoallelic change in @GENE$ (c.G680A, p.Arg227Gln, @VARIANT$:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of SRD5A2, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014).",5765430,SRD5A2;37292,SF1;138518,rs9332964;tmVar:rs9332964;VariantGroup:0;CorrespondingGene:6716;RS#:9332964,single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536,1
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"In the subject III.1, the variant, carried in the heterozygous status, is the c.868 G > T; @VARIANT$, in the glucokinase (@GENE$) gene; the III.2 subject carried the @VARIANT$; p.Pro291Arg, in the @GENE$ gene.",8306687,CGK;55964,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, SEC23A @VARIANT$ (p.M400I) and @GENE$ c.1000C>T (@VARIANT$), associated with congenital birth defects in two patients from a consanguineous family. Patients presented with carbohydrate-deficient transferrin, tall stature, obesity, macrocephaly, and maloccluded teeth. The parents were healthy heterozygous carriers for both mutations and an unaffected sibling with tall stature carried the heterozygous mutation in @GENE$ only.",4853519,MAN1B1;5230,SEC23A;4642,c.1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,p.R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and @VARIANT$; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, @VARIANT$, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.1556G>A;tmVar:c|SUB|G|1556|A;HGVS:c.1556G>A;VariantGroup:9;CorrespondingGene:4647;RS#:111033206;CA#:278629,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"In patient AVM226, we identified the compound heterozygous variants @VARIANT$ (p.Val1259Ile) and c.2966A>T (@VARIANT$) in @GENE$ (table 2). @GENE$ and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.",6161649,DSCAM;74393,DSCAML1;79549,c.3775G>A;tmVar:c|SUB|G|3775|A;HGVS:c.3775G>A;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,p.Gln989Leu;tmVar:p|SUB|Q|989|L;HGVS:p.Q989L;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (@VARIANT$) and @GENE$: @VARIANT$ (p.410T>M), @GENE$: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"On the basis of the data collected in this study, we may speculate that the presence of @GENE$-@VARIANT$, together with three @GENE$-@VARIANT$ alleles, could lead to an increased risk of developing cardiac arrhythmias due to the prolongation of the QT interval.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
"Moreover, patients carrying a LAMA4 @VARIANT$ mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in @GENE$ (L1038P) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,MYH7;68044,MYBPC3;215,Pro943Leu;tmVar:p|SUB|P|943|L;HGVS:p.P943L;VariantGroup:5;CorrespondingGene:3910;RS#:387907365;CA#:143749,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0
"Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in @GENE$ in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/MITF and GJB2/@GENE$ (group II). (A) In addition to c.235delC in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3.",4998745,MITF;4892,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"In patient AVM226, we identified the compound heterozygous variants c.3775G>A (p.Val1259Ile) and c.2966A>T (p.Gln989Leu) in @GENE$ (table 2). DSCAML1 and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,DSCAM;74393,PTPN13;7909,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in @GENE$ (p.N382S/@VARIANT$) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,MYO6;56417,GFI1;3854,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"The @VARIANT$ variant in GJB2 occurring in complex heterozygosity with a pathogenic @GENE$ variant, @VARIANT$ from SH175-389, suggests a possible digenic etiology of SNHL involving two different gap junction proteins, @GENE$ and Cx31.",4998745,GJB3;7338,Cx26;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Four genes (including @GENE$, @GENE$, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,AGXT2;12887,ZFHX3;21366,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"In the subject III.1, the variant, carried in the heterozygous status, is the c.868 G > T; @VARIANT$, in the @GENE$ (CGK) gene; the III.2 subject carried the c.872 C > G; @VARIANT$, in the @GENE$ gene.",8306687,glucokinase;55440,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2). While TIMP3 blocks VEGF/@GENE$ signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,RASA1;2168,VEGFR2;55639,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and @GENE$: @VARIANT$, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and @VARIANT$; PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and PITX2 variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,PITX2;55454,FOXC2;21091,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, DFNB3, and @GENE$, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in @GENE$ (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES.",4998745,DFNB16;15401,GJB2;2975,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"    CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in MYOD1 and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MYOD1;7857,TBX6;3389,c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,CDH23;11142,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"  Recently, Gifford et al., identified three missense variants in @GENE$ (@VARIANT$), MYH7 (Leu387Phe), and @GENE$ (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MKL2;40917,NKX2-5;1482;4824,Gln670His;tmVar:p|SUB|Q|670|H;HGVS:p.Q670H;VariantGroup:2;CorrespondingGene:57496,Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058,1
"In AS patient IID27, the two mutations in COL4A5 and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a).",6565573,COL4A4;20071,COL4A5;133559,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0
"The R171 and @VARIANT$ residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. @VARIANT$ is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of EDA with its receptors. Structure analysis of mutant residues in the three-dimensional EDA trimer. The @GENE$ trimer is shown as a ribbon with relevant side chains rendered in spheres. The G257 and I312 residues are in yellow and blue, respectively. The side chain of the R289 residue is represented by a colored stick. (A) The planform of the EDA trimer. (B) The side view of the EDA trimer. Discussion This is the first study to show that simultaneous WNT10A and EDA mutations could lead to tooth agenesis in the Chinese population. We found that six participants harbored digenic mutations in both @GENE$ and EDA: two of them had isolated oligodontia and the others had syndromic tooth agenesis.",3842385,EDA;1896,WNT10A;22525,G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216,I312;tmVar:p|Allele|I|312;VariantGroup:7;CorrespondingGene:1896,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the TNFRSF13B/@GENE$ C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The @GENE$ T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.",6707335,CCNF;1335,ALS2;23264,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"The proband in family PCG-139 also carried a rare PITX2 variant (@VARIANT$) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for CYP1B1 and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, CYP1B1: p.(E173*). M4, PITX2: @VARIANT$. M5, PITX2: p.(A188T). Arrows show the index cases. +: wild-type allele. The asterisk indicates a de novo PITX2 variant. Evolutionary conservation of @GENE$ and PITX2 variants Evolutionary amino acid or nucleotide sequence conservation analysis were assessed using a multiple sequence alignment of representative orthologous proteins or genes of seven different species, from fish to human. This analysis revealed that most FOXC2 and @GENE$ wild-type amino acids or nucleotides were highly conserved (Fig 4).",6338360,FOXC2;21091,PITX2;55454,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In this study, we performed whole-genome sequencing in 104 pathologically confirmed FTLD-TDP patients from the Mayo Clinic brain bank negative for @GENE$ and @GENE$ mutations and report on the contribution of rare single nucleotide and copy-number variants in 21 known neurodegenerative disease genes. Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1.",4470809,C9ORF72;10137,GRN;1577,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"The novel truncated variant in @GENE$ was not found in our ""in-house"" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The @VARIANT$ (p.R77C) variant in @GENE$ and @VARIANT$ (p.I80Gfs*13) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.",6637284,S100A13;7523,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 2;2975,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, @VARIANT$ and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.3719G>A;tmVar:c|SUB|G|3719|A;HGVS:c.3719G>A;VariantGroup:87;CorrespondingGene:4647;RS#:542400234;CA#:5545997,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"@GENE$ Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (rs121908073), and a novel variant, @VARIANT$ of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.W482R;tmVar:p|SUB|W|482|R;HGVS:p.W482R;VariantGroup:0;CorrespondingGene:117531;RS#:754142954;CA#:5081956,1
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"Mutations in @GENE$ and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (@VARIANT$; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in @GENE$. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1
"    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in @GENE$ (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.   CSS161458 had a heterozygous splicing variant c.156-1G>C in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).    DISCUSSION In this study, we performed exome sequencing on 584 patients with @GENE$ and without a molecular diagnosis.",7549550,MEOX1;3326,CS;56073,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling.",6161649,ENG;92,SCUBE2;36383,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes.     ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of WNT10A were detected.",3842385,WNT10A;22525,EDA;1896,p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"                                 CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. @GENE$ @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and SCN5A p.R1865H by WES and predisposing genes analyses. More cellular and animal research is needed to further investigate whether the coexisting interaction of KCNH2 @VARIANT$ and SCN5A p.R1865H increases the risk of the early-onset LQTS and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Two potential disease-causing mutations were identified: (d) ENAM: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) @GENE$ missense mutation c.1559G>A/@VARIANT$. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (@GENE$ and LAMA3) mutations.",6785452,LAMA3;18279,ENAM;9698,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,0
"Despite the absence of IgG detected in the supernatants of these cultures, no defect was observed in the generation of isotype switched IgG+ cells in II.2 (carrying both TNFRSF13B/@GENE$ @VARIANT$ and TCF3 @VARIANT$ mutations), compared to III.2, who has neither mutation. Her son, III.1, carrying the @GENE$ T168fsX191 mutation only, also generated a similar proportion of IgG+ switched cells.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"A total of 2 novel variants, @VARIANT$ and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The @GENE$ variant p.R450H was a recurrent inactivating mutation and p.C176R and p.K618 were novel. p.C176R is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and p.R528S and p.K618* are located in the cytoplasmic loops (Fig. S3C). Patients with GIS had a higher tendency to be affected with mutations than patients with TD [25/32 (78%) vs. 6/11 (54%), Fig. 2]. Variants in TG, TSHR, DUOXA2, SLC5A5 and PROP1 genes were found exclusively in patients with GIS, and 1 variant in @GENE$ was found in patients with TD.",7248516,TSHR;315,TRHR;20707,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,0
"Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys).",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"M1, CYP1B1: @VARIANT$. M2, @GENE$: p.(E387K). M3, CYP1B1: p.(E173*). M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(A179fs*18);tmVar:p|FS|A|179||18;HGVS:p.A179fsX18;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein. However, the two rare FUS variants (Y25C and P106L) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein. Although the majority of FUS mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging.       In the @GENE$ gene, a known missense variant (@VARIANT$) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel K631del deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The NEK1 @VARIANT$ variant was also present in this patient.",6707335,ubiquilin-2;81830,TBK1;22742,I397T;tmVar:p|SUB|I|397|T;HGVS:p.I397T;VariantGroup:11;CorrespondingGene:29110;RS#:755069538;CA#:6669001,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,0
"These results were confirmed for the His24Leu and @VARIANT$ variants when using the reporters for CYP11A1 and HSD17B3 (Figure 2B,C). In contrast, variant @VARIANT$ did not change the reporter activities of CYP11A1 and @GENE$ (Figure 2B,C). Expression of NR5A1 variants was assessed by Western blot in our cell model. As shown in Figure 2D, SF1 protein expression was similar for all studied NR5A1 variants. 3. Discussion Patients harboring NR5A1 variants manifest with extremely broad phenotypes, ranging from normal sex development to complete sex reversal. A lack of genotype-phenotype correlation has been widely questioned, and the hypothesis of additional genetic variations contributing to the complex and variable phenotype has been formulated. In this work, we report clinical and genetic data of seven 46,XY DSD patients with heterozygous NR5A1 variants with normal adrenal function. Using targeted gene panel analysis for sex development-related genes, we found a second likely disease causing/pathogenic variant in known DSD genes (STAR, @GENE$, ZFPM2) in three of six studied 46,XY DSD individuals, supporting the hypothesis of oligogenic disease.",7696449,HSD17B3;20089,AMH;68060,Cys30Ser;tmVar:p|SUB|C|30|S;HGVS:p.C30S;VariantGroup:5;CorrespondingGene:6662;RS#:1003847603;CA#:293780979,Cys301Tyr;tmVar:p|SUB|C|301|Y;HGVS:p.C301Y;VariantGroup:2;CorrespondingGene:6736,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,DCTN1;3011,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Moreover, the presence of other variants (KCNQ1-@VARIANT$, KCNH2-@VARIANT$, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. On the contrary, in the mother, some other factors, including unknown genetic modifiers, could counteract the functional impairment of mutant channels, thereby protecting the asymptomatic @GENE$-p.C108Y mutation-positive subject from arrhythmia susceptibility. We cannot rule out the presence, in this family, of other polymorphisms that alter the function of different ion channels. For example, SNPs in the @GENE$ gene have been associated with greatly deranged QT intervals in healthy subjects and in LQTS patients.",5578023,KCNH2;201,NOS1AP;136252,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,0
"Most had C9orf72 repeat expansion combined with another mutation (e.g. @GENE$ @VARIANT$ or @GENE$ A321V; Supplementary Table 6). A single control also had two mutations, P372R in ALS2 and @VARIANT$ in TARDBP.",5445258,VCP;5168,TARDBP;7221,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0
"Sequence alterations were detected in the COL6A3 (rs144651558), RYR1 (@VARIANT$), @GENE$ (rs138172448), and DES (@VARIANT$) genes. These variants were then screened in his sister who had inherited all variants except that found in the CAPN3 gene. The COL6A3 and @GENE$ variants were predicted to be benign by SIFT and PolyPhen and MutationTaster analysis.",6180278,CAPN3;52,RYR1;68069,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"In addition, we have confirmed that immunoreactive signal corresponding to the anti-ephrin-B2 antibody was colocalized with that to the anti-@GENE$ antibody in the inner ear (Supplementary Fig. 3g). These results suggest an important role of ephrin-B2 as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1.           Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, @VARIANT$ and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated @GENE$ triggered by ephrin-B2 stimulation.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Causative heterozygous mutations in @GENE$ (@VARIANT$/c.1145A > G) and @GENE$ (p.I1176L/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1. Sanger sequencing on available samples from consenting individuals was used for segregation analysis and confirmation of variants in individuals denoted by '+' and '#', respectively (b)                 Genotypes and phenotypes of various members in the family Individual GFI1 Blood MYO6 Hearing   III-1 N382S (het) Neutropenia, monocytosis I1176L (het) Impaired   III-3 WT Normal WT Normal   IV-1 N382S (het) Neutropenia, monocytosis I1176L (het) Impaired   IV-2 N382S (het) Neutropenia, monocytosis @VARIANT$ (het) Impaired",7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 2;2975,gap junction protein beta 3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT6;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"In this family, the @GENE$/TACI @VARIANT$ mutation appears to demonstrate a gene dosage effect on serum IgG levels. The brother who is homozygous (II.4) for the TNFRSF13B/TACI C104R mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1
"Importantly, he had no coexistent mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, @GENE$, GNRHR, @GENE$, or KISS1R. The second patient (KS male C7) had a heterozygous c.757G>A (p.Ala253Thr) mutation (Figure 1; Table 1) affecting a completely conserved Ala253 residue (Figures S1-4). Using multiple sequence alignment (ESPRESSO), a protein model for the N-terminus was constructed. Both SSPIDER and INTERPROSURF analysis (Figure S4) suggest functional importance for Ala253; and SIFT predicts a deleterious effect for p.Ala253Thr. Although p.Ala253Thr did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This @VARIANT$ mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously.",3888818,KAL1;55445,GNRH1;641,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"These data also indicate that an alternate pathway is used for quality control of pro-@GENE$ when MAN1B1 alpha-mannosidase activity is reduced. DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in @GENE$, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet.",4853519,COL1A1;73874,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB @VARIANT$, SCRIB p.G644V and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"The p.Ile312Met (@VARIANT$) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene. Variants in the @GENE$ gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the DYNC1H1 gene in fALS and sALS patients, suggesting its role in ALS. Based on our findings, we strengthen the potential link between DYNC1H1 variants and ALS.     Given that there are genetic and symptomatic overlaps among many neurodegenerative diseases, it has been suggested that causative variants might play roles in multiple disorders. Two heterozygous variants (@VARIANT$ and R166C) were detected in the GBE1 gene.",6707335,MATR3;7830,DYNC1H1;1053,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,H398R;tmVar:p|SUB|H|398|R;HGVS:p.H398R;VariantGroup:18;CorrespondingGene:2632;RS#:755004170;CA#:2499769,0
"Three variants of @GENE$ (NM_007123), @VARIANT$, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (@GENE$) identified in SH 94-208). However, this subject showed no retinal abnormalities and only manifested severe SNHL with a mean hearing threshold of 75 dB HL, which was not compatible with type II Usher syndrome. Therefore, these variants of USH2A were excluded as causative deafness mutations. SH94-208 also showed the G1748S variant of ANK1 (NM_000037). Structural variations such as large genomic deletions involving ANK1 at chromosome 8p11.2p12 can lead to contiguous syndrome, with SNHL as one of the symptoms. However, the @VARIANT$ variant of ANK1 was a point mutation, not a structural variation (see Table S4, Supplemental Content, which illustrates depth of coverage of TES).",4998745,USH2A;66151,ANK1;55427,R5143C;tmVar:p|SUB|R|5143|C;HGVS:p.R5143C;VariantGroup:6;CorrespondingGene:7399;RS#:145771342;CA#:182576,G1748S;tmVar:p|SUB|G|1748|S;HGVS:p.G1748S;VariantGroup:19;CorrespondingGene:286;RS#:746486928;CA#:4727361,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"    A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, was identified in patient #3. BBS1, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of BBS2 and @GENE$ lie in this portion. The variant in BBS7 is noteworthy, since very few Bardet-Biedl cases are reported in the literature. Indeed, only 35 variants in this gene are listed in the Human Gene Mutation Database (HGMD, https://portal.biobase-international.com/cgi-bin/portal/login.cgi). A homozygous substitution c.1235G > T in @GENE$, leading to p.(@VARIANT$), was also identified in an affected sibling of proband #12.",6567512,BBS7;12395,BBS6;10318,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,LQT2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"To investigate the effects of one candidate variant on mutant @GENE$ function, Western blotting and coimmunofluorescence were used to assess binding capacity, and leptomycin B exposure along with immunofluorescence was used to assess nuclear localization. Results: We describe a child who presented in infancy with combined pituitary hormone deficiencies and whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a WDR11 (@VARIANT$;p.I436V) mutation inherited from an unaffected father.",5505202,WDR11;41229,PROKR2;16368,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/@GENE$ @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The @GENE$ @VARIANT$ mutation was absent in the proband's parents, indicating a de novo origin.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"In patient AVM226, we identified the compound heterozygous variants c.3775G>A (@VARIANT$) and @VARIANT$ (p.Gln989Leu) in @GENE$ (table 2). @GENE$ and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.",6161649,DSCAM;74393,DSCAML1;79549,p.Val1259Ile;tmVar:p|SUB|V|1259|I;HGVS:p.V1259I;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,c.2966A>T;tmVar:c|SUB|A|2966|T;HGVS:c.2966A>T;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"While tagged versions of EphA2 @VARIANT$ and EphA2 T511M were effectively precipitated with Fc-fusion @GENE$ compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down EphA2 G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 G355R and EphA2 T511M with @GENE$ induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as @VARIANT$, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum.",7067772,ephrin-A1;3262,pendrin;20132,G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0
"The DNA sequencing chromatograms from the proband show two @GENE$ and one @GENE$ heterozygous mutations. While both LRP6 variants, p.(@VARIANT$) and p.(Asn1075Ser), were inherited from her father, the WNT10A mutation, @VARIANT$ was maternally derived.",8621929,LRP6;1747,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (c.1892C>T).",5887939,CELSR1;7665,CELSR2;1078,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/@GENE$ C104R mutations. Other family members who have inherited @GENE$ T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,KAL1;55445,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"(A) Segregation of the @GENE$-p.R583H, KCNH2-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNQ1;85014,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ @VARIANT$ and GFP-CYP1B1 E229K to immunoprecipitate HA-@GENE$ @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,1
"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"While both LRP6 variants, p.(@VARIANT$) and p.(Asn1075Ser), were inherited from her father, the WNT10A mutation, @VARIANT$ was maternally derived. (B) Dental phenotype of the proband (age ten) shows a mixed dentition with dental spacing over anterior sextants. Both primary and permanent teeth were of normal size and morphology. (C) Proband's panoramic radiograph shows a total of ten missing permanent teeth, involving primarily bicuspids and second molars. The roots of the molars were not particularly convergent or taurodontic.   Amino acid sequence alignment and structural prediction of LRP6 missense mutations. (A) Alignment of P1B3 domain (a.a. 140-177 of human LRP6). Methionine168 is extremely conserved throughout evolution. The p.(Met168Arg) mutation was predicted to be highly destabilizing. (B) Alignment of P3B3 domain (a.a. 750-787 of human LRP6). The Alanine754 is extremely conserved among orthologs of @GENE$ and @GENE$. The p.(Ala754Pro) mutation was predicted to be highly destabilizing.",8621929,LRP6;1747,LRP5;1746,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Two novel variants were found in @GENE$, including an indel (@VARIANT$) and a splice variant (IVS17+1G>T). The former variant caused the deletion of seven amino acids in exon 12 (p.R434_S440del). These seven amino acids are located in the peroxidase- (PO-) like domain and are conserved among DUOX2 orthologs (Figure 2 and Figure S1). The latter variant likely resulted in aberrant splicing of the transcript. Two novel variants were identified in @GENE$, including one frameshift mutation (@VARIANT$, p.C687LfsX34) and one missense mutation (c.1514G>A, p.G505D).",6098846,DUOX2;9689,TG;2430,c.1300_1320delCGAGATATGGGGCTGCCCAGC;tmVar:c|DEL|1300_1320|CGAGATATGGGGCTGCCCAGC;HGVS:c.1300_1320delCGAGATATGGGGCTGCCCAGC;VariantGroup:75;CorrespondingGene:50506,c.2060_2060delG;tmVar:c|DEL|2060_2060|G;HGVS:c.2060_2060delG;VariantGroup:68;CorrespondingGene:405753,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Similarly, our results indicate that increased transactivation associated with the @VARIANT$ PITX2 mutation is not related with altered protein stability, protein conformation or subcellular localization. Proline possesses a hydrophobic side chain, whereas threonine side chain has both hydrophilic and hydrophobic functions. Therefore, this amino acid replacement may affect protein interactions taking place in the transcriptional inhibitory domain where it is located, leading to increased @GENE$ activity. In this line, an increased side chain polarity associated with amino acid substitution p.(A188T) could also interfere protein interactions involving the first PITX2 transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, FOXC2 variants p.S36S (synonymous) and @VARIANT$ (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and FOXC2-AS1 genes. @GENE$-AS1 encodes a lncRNA transcribed from the negative strand of FOXC2.",6338360,PITX2;55454,FOXC2;21091,p.P179T;tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,c.*38T>G;tmVar:c|SUB|T|*38|G;HGVS:c.*38T>G;VariantGroup:6;CorrespondingGene:103752587;RS#:199552394,0
"Below symbols are indicated genotypes for @GENE$ and @GENE$, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, CYP1B1: @VARIANT$. M3, CYP1B1: p.(E173*). M4, PITX2: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"M1, CYP1B1: @VARIANT$. M2, CYP1B1: p.(E387K). M3, @GENE$: p.(E173*). M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(A179fs*18);tmVar:p|FS|A|179||18;HGVS:p.A179fsX18;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Patient 3 was found to harbor a previously reported @VARIANT$ variant in @GENE$, alongside a rare variant in ZFPM2 (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in @GENE$ (c.G680A, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a single codon deletion at position 372 of NR5A1 (Table 3).",5765430,NR5A1;3638,SRD5A2;37292,p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,0
"The effects of @GENE$-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation. Conclusions Our results demonstrated that the loss-of-function CACNA1C-@VARIANT$ mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in @GENE$/TGF-beta signalling.",6161649,MAP4K4;7442,BMP;55955,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and @GENE$ (c.9921T>G).",3125325,CDH23;11142,USH2A;66151,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"@GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2).",6161649,SCUBE2;36383,RASA1;2168,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0
"Six variants in PKD1 occurred de-novo, three of which were not previously described: c.3236del p.(Asp1079Alafs*25), @VARIANT$ p.(Glu2954*), and c.9201+1G>A. One de-novo and novel variant was also detected in PKD2: c.992G>A p.(@VARIANT$). Types of 158 distinct possible pathogenic variants detected in @GENE$ and @GENE$ genes.",7224062,PKD1;250,PKD2;20104,c.8860G>T;tmVar:c|SUB|G|8860|T;HGVS:c.8860G>T;VariantGroup:46;CorrespondingGene:5310,Cys331Tyr;tmVar:p|SUB|C|331|Y;HGVS:p.C331Y;VariantGroup:1;CorrespondingGene:23193;RS#:144118755,0
"(b) Electropherograms of unaffected family member (II-1) and proband (II-2) show @GENE$ variant. (c) Multiple sequence alignment shows evolutionary conservation of Thr330 among vertebrates. (d) Electropherograms of unaffected family member (II-1) and proband (II-2) show @GENE$ variant. (e) Multiple sequence alignment shows evolutionary conservation of @VARIANT$ among vertebrates               A GNA14 frameshift variant (@VARIANT$ [NM_004297.3], p.Thr330ArgfsTer67 [NP_004288.1]) was also identified in the same pedigree (Family 10043) and is present at low frequency in gnomAD (1.23E-05) (Figure 6; Tables 1, 5, and 8 and S2; Data S1).",6081235,GNA14;68386,HS1BP3;10980,Gly32;tmVar:p|Allele|G|32;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"    A new pathogenic variant in @GENE$ affecting a conserved residue in the functional domain of BBsome protein (@VARIANT$; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, @VARIANT$, was identified in patient #3.",6567512,BBS2;12122,BBS7;12395,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,KCNE2;71688,LQT2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, DVL3 p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  @GENE$, 23  @GENE$, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS.",7689793,EBNA1BP2;4969,TRIP6;37757,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"  Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in SQSTM1 (@VARIANT$) and a variant in @GENE$ (@VARIANT$). At the time of this report, only a single prior myopathy case with the same genetic variants has been reported, but the clinical and myopathological features were not illustrated. There are also two further cases of MRV having the same TIA1 variant but a different SQSTM1 mutation (c.1165+1G>A), one of whom was previously reported as having a @GENE$-MRV.",5868303,TIA1;20692,SQSTM1;31202,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"However, the KS patient carrying the @VARIANT$ mutation in @GENE$ suffers from a severe sleep disorder and marked obesity, which might be related to the known circadian function of prokineticin-2 and its potential roles in sleep-wake regulation and ingestive behavior. In human monogenic disorders, genuine dominance, where heterozygotes and homozygotes have the same phenotype, is unusual. In particular, most dominant developmental diseases are far more severe in the homozygous state. Therefore, the finding of both heterozygous and homozygous (or compound heterozygous) KS patients for a given mutation in @GENE$ (e.g., @VARIANT$ or p.L173R, see Table 1) is quite remarkable and raises the question of a possible digenic mode of inheritance in heterozygous patients.",161730,PROK2;9268,PROKR2;16368,p.R73C;tmVar:p|SUB|R|73|C;HGVS:p.R73C;VariantGroup:1;CorrespondingGene:60675;RS#:121434272;CA#:252842,p.R85H;tmVar:p|SUB|R|85|H;HGVS:p.R85H;VariantGroup:0;CorrespondingGene:128674;RS#:1347675599,0
The variant pair @GENE$ (@VARIANT$)-@GENE$ (@VARIANT$) was classified by ORVAL as true digenic.,8446458,CCDC141;52149,PROKR2;16368,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,c.868C > T;tmVar:c|SUB|C|868|T;HGVS:c.868C>T;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257,1
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"  To gain further insight into the role of @GENE$ on pendrin regulation, pendrin A372V, L445W, Q446R or G672E was co-overexpressed with EphA2. The cells were transfected with cDNAs of encoding myc-pendrin diease forms with that of EphA2, and the non-permeable cells were stained with an anti-myc antibody. While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, @VARIANT$, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-@GENE$ A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), @VARIANT$ (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,EphA2;20929,pendrin;20132,Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777,Ser166 to Asn;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Additionally, a novel variant (@VARIANT$) in the 5' untranslated region of the @GENE$ gene was also detected. As the screening of untranslated regions was not in the scope of our research, we did not examine it further.   No @GENE$ and TARDBP gene variants were found in this cohort. We would like to point out that 37 of the analyzed samples were overlapping samples from a previous study and were known to be negative for SOD1 and TARDBP mutations. Still, based on earlier results, one would expect to detect SOD1 variants in the further 70 samples. Variants Detected in Minor ALS Genes By focusing on the analysis of minor ALS genes, 33 variants (31 missense and 2 splicing) were detected in 26 genes corresponding to 29 patients (27.1% of all patients,  Supplementary Table 2 ). No patients were identified as being homozygous for any of the detected variants. A patient was carrying two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene; both variants localized in the motor domain of the protein.",6707335,FUS;2521,SOD1;392,c.-25C > T;tmVar:c|SUB|C|-25|T;HGVS:c.-25C>T;VariantGroup:38;CorrespondingGene:2521,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"        Molecular Data All three probands carry two heterozygous variants: @GENE$, @VARIANT$ (p.Pro392Leu), and @GENE$, @VARIANT$ (p.Asn357Ser).",5868303,SQSTM1;31202,TIA1;20692,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (@VARIANT$; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, @GENE$, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,SNAI3;8500,ZNRF3;46592,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Our data indicate that a normal level of MAN1B1 is required to prevent secretion of abnormally folded pro-@GENE$. These data also indicate that an alternate pathway is used for quality control of pro-COL1A1 when MAN1B1 alpha-mannosidase activity is reduced. DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in @GENE$, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet.",4853519,COL1A1;73874,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,LQT2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"        Molecular Data All three probands carry two heterozygous variants: SQSTM1, c.1175C>T (@VARIANT$), and TIA1, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and SQSTM1 variants have been reported in multiple databases. The @GENE$ variant is designated as rs104893941 in dbSNP and reported at allele frequencies of 0.0009 in the Exome Aggregation Consortium database (ExAC), 0.0024 in 1,000 Genomes Project database (TGP), and 0.0015 in the NHLBI GO Exome Sequencing Project (GO-ESP) (accessed January 23, 2018) and is more frequent in certain European populations.",5868303,TIA1;20692,SQSTM1;31202,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and @GENE$-c.G1748A (@VARIANT$) were introduced into @GENE$ and KCNQ1 cDNAs, respectively, as described previously.",5578023,KCNQ1;85014,KCNH2;201,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"We observed that isoproterenol could enhance the activity of LTCC in the HEK293T cells, which may be associated with the evocation of @GENE$/protein kinase A pathways by the activation of the endogenous @GENE$ adrenoreceptors. In summary, we investigated an extremely rare large ERS family with a high incidence of nocturnal SCD, in which we found a pathogenic mutation in CACNA1C (@VARIANT$) with loss-of-function. The penetrance was also incomplete, which was modified by a gain-of-functional SCN5A-@VARIANT$ variant and sex.",5426766,cAMP;110678,beta2;4257,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, @VARIANT$), @GENE$ @VARIANT$ (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,SCN5A;22738,LAMA2;37306,c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0
"The pathogenicity of the @VARIANT$ mutation in @GENE$  is, however, questionable since we found it in five alleles from the control population. The @VARIANT$ mutation in PCDH15, leading to an in frame-deletion of a threonine residue (p.T1868del) within the intracellular domain of the @GENE$ CD1 isoform, also warrants a special mention.",3125325,CDH23;11142,protocadherin-15;23401,p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387,c.5601delAAC;tmVar:p|DEL|C.5601|N;HGVS:p.C.5601delN;VariantGroup:316;CorrespondingGene:65217,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and TAF15 p.R408C with @GENE$ @VARIANT$ and SETX p.T14I).,4293318,VAPB;36163,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (p.R559W) and @GENE$: c.7942G > A (@VARIANT$), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,p.G2648S;tmVar:p|SUB|G|2648|S;HGVS:p.G2648S;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,TACR3;824,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"In the subject III.1, the variant, carried in the heterozygous status, is the c.868 G > T; @VARIANT$, in the @GENE$ (@GENE$) gene; the III.2 subject carried the @VARIANT$; p.Pro291Arg, in the HNF1A gene.",8306687,glucokinase;55440,CGK;55964,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"KCNH2-@VARIANT$ homozygous tetramers and @GENE$-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in IMP4 (OMIM 612981; @VARIANT$, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in UBR4 (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and ARHGEF19 (OMIM 612496; rs144638812, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus. To date, @GENE$ and @GENE$ have not been linked to a medical disorder.",6081235,IMP4;68891,ARHGEF19;17710,rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,0
"Two novel @GENE$ frameshift mutations were identified. A single-nucleotide duplication (c.395dupA/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (@VARIANT$/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (@VARIANT$/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (c.1559G>A/p.Cys520Tyr) that cosegregated with both the AI phenotype and the ENAM mutation.",6785452,ENAM;9698,LAMA3;18279,c.2763delT;tmVar:c|DEL|2763|T;HGVS:c.2763delT;VariantGroup:0;CorrespondingGene:10117;RS#:529979202,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD6;2617,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,0
"In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD.  Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.1051 G > A @VARIANT$), have already been described in the literature.",3975370,IL10RA;1196,IL10RB;523,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,p.G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and @VARIANT$ variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"All but 1 patient had a @GENE$ mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 @GENE$ variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and @VARIANT$ and p.K618 were novel.",7248516,TPO;461,TSHR;315,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the @GENE$ gene (LQT6).",6610752,LQT2;201,KCNE2;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,TACR3;824,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis.         We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: 179260153C/T, refSNP ID rs4935; Chr5: 179260213G/A, rs4797; Chr5: @VARIANT$, rs10277; Ch5: 179264915G/T, rs1065154 ].",5868303,TIA1;20692,SQSTM1;31202,c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,179264731T/C;tmVar:c|SUB|T|179264731|C;HGVS:c.179264731T>C;VariantGroup:4;CorrespondingGene:8878;RS#:10277;CA#:3601068,0
"  This patient also was found to have a novel, heterozygous TACR3 nonsense mutation @VARIANT$ not seen in 180 controls (Figure 1C; Table 1). Trp275 lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this G-protein coupled receptor, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in CHD7, FGF8, @GENE$, PROK2, @GENE$, TAC3, KAL1, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to @VARIANT$ ;p.Thr478Ala from NP_056352).",3888818,FGFR1;69065,PROKR2;16368,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,c.1432A>G;tmVar:c|SUB|A|1432|G;HGVS:c.1432A>G;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,0
"Her in vitro IgG production is substantially lower than that of her @GENE$/TACI @VARIANT$ heterozygous brother (II.3) and her @GENE$ @VARIANT$ heterozygous son (III.1), who individually bear each mutation.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1
"The MYH7 @VARIANT$ variant is well described and classified as pathogenic in ClinVar and the Atlas of Cardiac Genetic Variation.                 4. Discussion Here we used targeted sequencing of 181 cardiomyopathy-related genes to identify the underlying genetic causes in three unrelated consanguineous families with DCM. We identified variants in two genes in family A. The first variant is p.Glu924Lys in @GENE$, a well-documented missense variant that has been classified as pathogenic in its association with HCM and previously reported in the Atlas of Cardiac Genetic Variation and ClinVar. The second variant is a novel, missense variant in @GENE$ (@VARIANT$), not reported in control databases including gnomAD, GME Variome, and dbSNP.",6359299,MYH7;68044,LAMA4;37604,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The @VARIANT$ variant alters an amino acid that is highly conserved among vertebrates (Figure 5). Another candidate variant in @GENE$ (rs7807826) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of MYH13 is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: c.2059C>T, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs.",6081235,MYH13;55780,NOS2;55473,Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in @GENE$, @VARIANT$ in SETDB1 and @VARIANT$ in S100A3, and one novel variant in @GENE$, were identified.",6637284,ISG20L2;12814,S100A13;7523,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Here, we found that pendrin @VARIANT$, L445W, Q446R, and G672E did not bind to EphA2. Given the fact that loss of @GENE$ disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of pendrin with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of @GENE$ from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with EphA2. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after ephrin-B2 stimulation.",7067772,EphA2;20929,pendrin;20132,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly).",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,1
"(A) In addition to @VARIANT$ in GJB2, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the @GENE$ locus.",4998745,MITF;4892,DFNB1;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Her in vitro IgG production is substantially lower than that of her TNFRSF13B/@GENE$ @VARIANT$ heterozygous brother (II.3) and her @GENE$ @VARIANT$ heterozygous son (III.1), who individually bear each mutation.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"During mesoderm development, the expression of @GENE$ is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.   CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in @GENE$ was also identified.",7549550,MEOX1;3326,MYOD1;7857,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,ANG;74385,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"The @VARIANT$ residue of MITF is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in @GENE$ in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of @GENE$/MITF and GJB2/GJB3 (group II). (A) In addition to c.235delC in GJB2, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3.",4998745,MITF;4892,GJB2;2975,p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In our study, @VARIANT$(p. Arg631*) and c.1267C > T(p. Arg423*) were the two reported variants, while c.1525delA(p. Ser509fs) and @VARIANT$(p. Ser509fs) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of @GENE$ gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function.         Prokineticin-2 (PROK2) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor @GENE$. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the PROKR2 and PROKR2 genes, which can be passed down through autosomal dominant or oligogenic inheritance.",8796337,KAl1;55445,PROKR2;16368,c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223,c.1524del A;tmVar:c|DEL|1524|A;HGVS:c.1524delA;VariantGroup:17;CorrespondingGene:3730,0
"We also identified a monoallelic change in @GENE$ (c.G680A, @VARIANT$, rs9332964:G>A) in Patient 11, who also harbored a @VARIANT$ of @GENE$ (Table 3).",5765430,SRD5A2;37292,NR5A1;3638,p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681,single codon deletion at position 372;tmVar:|Allele|SINGLECODON|CODON372;VariantGroup:21;CorrespondingGene:2516,1
"The HNF1A P291fsinsC (@VARIANT$) mutation is the most common mutation causing HNF1A-MODY, described in 234 families and the HNF4A @VARIANT$ mutation is the most common mutation causing HNF4AMODY, described in 15 families throughout the world (Colclough K et al. 2012, submitted to Human Mutation). Digenic cases are likely to be very rare, but may be under ascertained due to sequential gene testing in molecular genetic laboratories meaning that if an @GENE$ mutation is found, @GENE$ analysis is not undertaken.",4090307,HNF1A;459,HNF4A;395,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
"    CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in MYOD1 and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.",7549550,MEOX1;3326,MYOD1;7857,c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Table 4 shows detailed information on the 10 rare missense variants, including: CELSR1 c.8772G > C (p.Q2924H); CELSR1 c.3364G > A (p.G1122S); CELSR1 c.3169C > T (p.R1057C); CELSR1 c.2305C > T (p.R769W); @GENE$ c.443G > A (p.R148Q); PTK7 @VARIANT$ (p.P642R); SCRIB c.3323G > A (p.G1108E); @GENE$ c.3131G > A (p.R1044Q); SCRIB c.1931G > T (@VARIANT$); and SCRIB c.1853A > G (p.K618R).",5966321,DVL3;20928,SCRIB;44228,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G644 V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, @VARIANT$), and DMD @VARIANT$ (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous @GENE$ p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,p.E1028V;tmVar:p|SUB|E|1028|V;HGVS:p.E1028V;VariantGroup:5;CorrespondingGene:3757,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, @VARIANT$) and @GENE$ (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"M1, @GENE$: @VARIANT$. M2, CYP1B1: p.(E387K). M3, CYP1B1: p.(E173*). M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(A179fs*18);tmVar:p|FS|A|179||18;HGVS:p.A179fsX18;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"NOD2, localized at chromosome 16q21, codify for a protein that belongs to the family of intracellular NLR (NOD-like receptors), able to recognize microbial components and to stimulate an inflammatory response through the activation of @GENE$. Moreover, three @GENE$ mutations (rs2066844, @VARIANT$ and @VARIANT$) represent the main genetic factor causing susceptibility to CD.",3975370,NF-kappaB;2971,NOD2;11156,rs2066845;tmVar:rs2066845;VariantGroup:9;CorrespondingGene:64127;RS#:2066845,rs5743293;tmVar:rs5743293;VariantGroup:18;RS#:5743293,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB3;7338,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"    A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, was identified in patient #3. BBS1, @GENE$ and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS2;12122,BBS7;12395,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"The SLC20A2 @VARIANT$ (p.His596Arg) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to @GENE$ dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the @GENE$ c.317G>C (@VARIANT$) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,PiT2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, @VARIANT$, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"On the other hand, EphA2 overexpression did not affect localization of @VARIANT$.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both @GENE$ recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA.",7067772,pendrin;20132,EPHA2;20929,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) GBE1 R524Ter; 2) @GENE$ G407RfrTer14; 3) NUBPL IVS8DC; 4) OAT Y299Ter. Two additional variants, @VARIANT$ in @GENE$ and @VARIANT$ in CACNA1S, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,PCCB;447,RYR1;68069,p. T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0
"Except II: 1, other family members did not carry @GENE$ mutation. (b, c), The ECG images of II: 1 demonstrated LQTS. QTc interval was 550 milliseconds (ms) when the heart rate was 79 bpm. It was 560 ms when the heart rate was 131 bpm. (d-f), Representative ECGs of family members of the proband (the chest lead V6 of II: 2 fell off). (g) The proband experienced multiple ventricular tachycardias and even ventricular fibrillation by ICD monitoring. ICD had released cardioversion and defibrillation treatment. (h) The Holter presented sinus arrest with persistent ventricular pacing of ICD        WES and predisposing gene analysis There were 552 variantss in exon and splicing regions by WES. Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ @VARIANT$ (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,KCNH2;201,LAMA2;37306,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The @GENE$ variant is designated as @VARIANT$ and reported at allele frequencies of 0.0071 in ExAC, 0.0016 in TGP, and 0.0068 in GO-ESP (accessed January 23, 2018). We examined the genotype data in the TGP to determine whether these variants coincide in controls. None of 2,504 self-declared healthy individuals in TGP has both TIA1, c.1070A > G (p.Asn357Ser) and @GENE$, @VARIANT$ (p.Pro392Leu).",5868303,TIA1;20692,SQSTM1;31202,rs116621885;tmVar:rs116621885;VariantGroup:5;CorrespondingGene:7072;RS#:116621885,c.1175C > T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, @VARIANT$, in one of the c.235delC carriers (SH107-225) (Figure 4A). She inherited @VARIANT$ of @GENE$ from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B).",4998745,MITF;4892,GJB2;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,VPS13C;41188,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and @GENE$ (@VARIANT$). Her father carries the mutations in @GENE$ and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,USH2A;66151,MYO7A;219,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and @GENE$-c.G1748A (@VARIANT$) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously. Primers used for mutagenesis are available upon request. The @GENE$-WT, KCNQ1-WT, and mutant coding sequences were engineered in bicistronic mammalian vectors pIRES2-EGFP (Biosciences-Clontech, Palo Alto, CA, USA).",5578023,KCNQ1;85014,KCNH2;201,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"A rare variant in @GENE$, @VARIANT$; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported @GENE$/FOG2 (@VARIANT$; p.Met544Ile) pathogenic missense alteration was identified.",7696449,AMH;68060,ZFPM2;8008,c.428C>T;tmVar:c|SUB|C|428|T;HGVS:c.428C>T;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,c.1632G>A;tmVar:c|SUB|G|1632|A;HGVS:c.1632G>A;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein. However, the two rare FUS variants (@VARIANT$ and P106L) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein.",6707335,SPG11;41614,ubiquilin-2;81830,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,Y25C;tmVar:p|SUB|Y|25|C;HGVS:p.Y25C;VariantGroup:12;CorrespondingGene:2521;RS#:141516414;CA#:8023442,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the @VARIANT$ of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Thirteen (72.2%) of 18 patients were identified eleven variants in eight known causative genes, namely @GENE$ (AXL), coiled-coil domain containing 141 (CCDC141), chromodomain helicase DNA binding protein 7 (CHD7), Dmx like 2 (DMXL2), fibroblast growth factor receptor 1 (FGFR1), patatin like phospholipase domain containing 6 (PNPLA6), RNA polymerase III subunit A (POLR3A) and prokineticin receptor 2 (PROKR2), see (Table 1 and 2). The PROKR2 missense variant p. Trp178Ser was recurrently observed in three patients, and was statistically enriched in our IHH cohort compared to the population (3/18 in the IHH cases vs 56/9976 in the gnomAD East Asians, P = 0.00015, one-tailed Fisher's exact test). Furthermore, another @GENE$ missense variant @VARIANT$ was identified in case P15. All of the remaining deleterious variants in the other seven known IHH genes were novel and unreported. Notably, the novel LoF variant FGFR1 @VARIANT$ in case P05 is de novo and evaluated as pathogenic.",8152424,AXL receptor tyrosine kinase;7583,PROKR2;16368,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Genotypes: @GENE$ @VARIANT$ (T1100M; blue); @GENE$ @VARIANT$ (Y179C; green); -, wild type.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0
"Her mother with c.1339 + 3A>T in @GENE$ and her father with a missense mutation c.4421C > T in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes.",6565573,COL4A5;133559,COL4A4;20071,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, @GENE$-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of KCNH2 @VARIANT$ and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous @GENE$ p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,LAMA2;37306,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"                    By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). This 2-year-old female showed severe autosomal recessive SNHL with a mean hearing threshold of 87.5 dB HL.   Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the @VARIANT$ variant of GJB2. The pathogenic potential of the p.T123N variant is controversial. Three variants of USH2A (NM_007123), R5143C, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and @GENE$ (ANK1) identified in SH 94-208).",4998745,USH2A;66151,Ankyrin 1;55427,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Additionally, a novel variant (@VARIANT$) in the 5' untranslated region of the FUS gene was also detected. As the screening of untranslated regions was not in the scope of our research, we did not examine it further.   No SOD1 and @GENE$ gene variants were found in this cohort. We would like to point out that 37 of the analyzed samples were overlapping samples from a previous study and were known to be negative for SOD1 and TARDBP mutations. Still, based on earlier results, one would expect to detect SOD1 variants in the further 70 samples. Variants Detected in Minor ALS Genes By focusing on the analysis of minor ALS genes, 33 variants (31 missense and 2 splicing) were detected in 26 genes corresponding to 29 patients (27.1% of all patients,  Supplementary Table 2 ). No patients were identified as being homozygous for any of the detected variants. A patient was carrying two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene; both variants localized in the motor domain of the protein.",6707335,TARDBP;7221,DYNC1H1;1053,c.-25C > T;tmVar:c|SUB|C|-25|T;HGVS:c.-25C>T;VariantGroup:38;CorrespondingGene:2521,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the @GENE$ gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,KCNE2;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with @GENE$ p.M170I and TAF15 p.R408C with SETX @VARIANT$ and SETX p.T14I).,4293318,ANG;74385,VAPB;36163,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS2;12122,BBS7;12395,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"@GENE$ @VARIANT$ but not @GENE$ @VARIANT$ causes cardiac defects in Drosophila Since the presence of SRNS and heart defects in family A was the main phenotypic difference from the other families, we looked more specifically into the cardiac and renal system of the fly.",5973622,KAT2B;20834,ADD3;40893,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"We defined the causal variants in 12 patients (60%) (Table 1); 5 patients were confirmed to have a compound heterozygous variant in a @GENE$ gene, while 7 patients where homozygous for the causative variant. In four cases the pathogenic variants were novel. We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS;12122,BBS6;10318,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"She inherited @VARIANT$ of @GENE$ from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). The @VARIANT$ residue of @GENE$ is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C).",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,CACNA1A;56383,HS1BP3;10980,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,0
"We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous @GENE$ mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,gap junction protein beta 6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Two unaffected subjects, SH60-137 and SH60-139, also carried @VARIANT$ in WFS1. This indicates that neither p.R143W in GJB2 nor p.D771N in WFS1 contributed to SNHL in SH60-136 and that p.R143W in GJB2 was an incidentally detected variant in this subject. GJB2 = gap junction protein beta 2, SNHL = sensorineural hearing loss, WFS1 = wolfram syndrome 1.             Single Heterozygous GJB2 Mutant Allele Possibly Contributing to Deafness via Digenic Inheritance: Double Heterozygosity with Additional Mutation in Other Deafness Genes (Group II) Interestingly, two subjects (SH107-225 and SH175-389) showed double heterozygosity for a GJB2 mutation and another likely pathogenic mutation in another deafness gene. We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, p.R341C, in one of the c.235delC carriers (SH107-225) (Figure 4A). She inherited @VARIANT$ of @GENE$ from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B).",4998745,MITF;4892,GJB2;2975,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
"These mutations are expected to affect the three classes of @GENE$ isoforms (Tables 2, 3, Figure 1). Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A), a novel nucleotide deletion (c.6404_6405delAG; p.E2135fsX31), and six missense mutations, four of which (p.R1189W, p.R1379P, @VARIANT$, and @VARIANT$) had not been previously reported.",3125325,harmonin;77476,CDH23;11142,p.D2639G;tmVar:p|SUB|D|2639|G;HGVS:p.D2639G;VariantGroup:219;CorrespondingGene:65217,p.R3043W;tmVar:p|SUB|R|3043|W;HGVS:p.R3043W;VariantGroup:141;CorrespondingGene:64072;RS#:375907609;CA#:5546888,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS2;12122,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"A PCR amplicon containing @GENE$ exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (@VARIANT$), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (@VARIANT$;[=]) (p.Arg80Cys) in the @GENE$ gene.",5527354,GNRHR;350,PROKR2;16368,rs373270328;tmVar:rs373270328;VariantGroup:0;CorrespondingGene:2798;RS#:373270328,c.[238C > T];tmVar:c|SUB|C|238|T;HGVS:c.238C>T;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,1
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, @VARIANT$ (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father).",3975370,IL10RA;1196,NOD2;11156,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,1
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$).",6610752,LQT2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,1
"She inherited @VARIANT$ of GJB2 from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). The @VARIANT$ residue of MITF is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/MITF and @GENE$/@GENE$ (group II).",4998745,GJB2;2975,GJB3;7338,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"To examine whether these mutations affect the ligand-binding specificity of @GENE$ to ephrin-A and ephrin-B, a pull down assay was performed with HEK293T cells due to their low level of endogenous EphA2 expression (Supplementary Fig 7a, b). While tagged versions of EphA2 G355R and EphA2 T511M were effectively precipitated with Fc-fusion @GENE$ compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down EphA2 G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 @VARIANT$ and EphA2 T511M with pendrin induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as @VARIANT$, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum.",7067772,EphA2;20929,ephrin-A1;3262,G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0
"Sequence alterations were detected in the COL6A3 (rs144651558), @GENE$ (@VARIANT$), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,RYR1;68069,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"(b) The changed site of SCN5A gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant DISCUSSION In our study, the proband with overlapped phenotypes of young early-onset LQTS and sinoatrial node dysfunction was first demonstrated to carry with the digenic heterozygous and pathogenic mutations of KCNH2 p.307_308del and @GENE$ p.R1865H. @GENE$ @VARIANT$ induced a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized, which thus mainly caused LQTS. The SCN5A @VARIANT$ slightly increased the molecular weight and aliphatic index, but reduced the instability index of Nav1.5 protein property, which potentially induced subsequent sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ @VARIANT$ to immunoprecipitate HA-@GENE$ @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the @VARIANT$ (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of Cx31 and Cx26 in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against @GENE$ (a) and @GENE$ (b).,2737700,Cx26;2975,Cx31;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,497A>G;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Patient P0418 carries a nonsense mutation in @GENE$ (p.S5030X) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the @GENE$ mutation. Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23.",3125325,USH2A;66151,MYO7A;219,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (@VARIANT$;[=]) (p.Arg80Cys) in the @GENE$ gene.         The @GENE$ frameshift mutation was identified in two different families and has not been reported before. It consists of an 11 base-pair deletion (@VARIANT$), and if translated, would be expected to result in a truncated protein due to a premature termination codon (p.Phe313Metfs*3).",5527354,PROKR2;16368,GNRHR;350,c.[238C > T];tmVar:c|SUB|C|238|T;HGVS:c.238C>T;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,c.937_947delTTTTTAAACCC;tmVar:c|DEL|937_947|TTTTTAAACCC;HGVS:c.937_947delTTTTTAAACCC;VariantGroup:7;CorrespondingGene:2798,1
"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, p. A85P, p.L86F, @VARIANT$, p.R127L, @VARIANT$, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,FOXC1;20373,PITX2;55454,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,p.G149D;tmVar:p|SUB|G|149|D;HGVS:p.G149D;VariantGroup:15;CorrespondingGene:1805;RS#:777651623,0
"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (@VARIANT$) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, @GENE$, @GENE$, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TG;2430,DUOX2;9689,p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0
(D) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (@VARIANT$) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$).,7279190,FLNB;37480,OFD1;2677,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,1
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,MAP4K4;7442,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the @GENE$ repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX @VARIANT$).",4293318,C9ORF72;10137,SOD1;392,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a WDR11 (@VARIANT$;p.I436V) mutation inherited from an unaffected father. Mutant @GENE$ loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus.",5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,VPS13C;41188,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,alsin;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,UBQLN2;81830,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The @GENE$ P291fsinsC (@VARIANT$) mutation is the most common mutation causing HNF1A-MODY, described in 234 families and the @GENE$ @VARIANT$ mutation is the most common mutation causing HNF4AMODY, described in 15 families throughout the world (Colclough K et al. 2012, submitted to Human Mutation).",4090307,HNF1A;459,HNF4A;395,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB2;2975,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Using phenotype-genotype analysis, we found that although patient S3 and her mother had the same mutation (heterozygous @GENE$ @VARIANT$ mutation and heterozygous @GENE$ @VARIANT$ mutation), patient S3 showed typical phenotypic expression of HED while her mother only had microdontia. Because the EDA mutation is the most frequent pathogenic cause of XLHED and the EDA gene is located on chromosome X, most female carriers of EDA mutations present with a normal or very mild phenotype.",3842385,EDA;1896,WNT10A;22525,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK @VARIANT$ (~70%). No significant change was observed with HA-@GENE$ G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2).,5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$).",5887939,DVL3;20928,SCRIB;44228,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with @GENE$ @VARIANT$ and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I).,4293318,ANG;74385,VAPB;36163,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,1
"@VARIANT$ carriers required different surgical procedures for correct IOP control (Table 2). This nucleotide substitution also mapped at FOXC2-AS1 intron 1 (@VARIANT$) and the regulatory feature (promoter) (Fig 1C), and it was inferred to produce a low functional effect on @GENE$ and a modifier outcome on both @GENE$ and the overlapping promoter.",6338360,FOXC2;21091,FOXC2-AS1;103752587;2303;5729,p.(S36S);tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260,n.145+174G>A;tmVar:n|SUB|G|145_174|A;VariantGroup:14;CorrespondingGene:5729,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB6;4936,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Notably, the patients carrying the @VARIANT$ and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,0
"The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene. Variants in the DYNC1H1 gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the DYNC1H1 gene in fALS and sALS patients, suggesting its role in ALS. Based on our findings, we strengthen the potential link between DYNC1H1 variants and ALS.     Given that there are genetic and symptomatic overlaps among many neurodegenerative diseases, it has been suggested that causative variants might play roles in multiple disorders. Two heterozygous variants (H398R and @VARIANT$) were detected in the GBE1 gene.",6707335,MATR3;7830,DYNC1H1;1053,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,R166C;tmVar:p|SUB|R|166|C;HGVS:p.R166C;VariantGroup:21;CorrespondingGene:2632;RS#:376546162;CA#:2499951,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We identified four genetic variants (@GENE$-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and @GENE$-@VARIANT$) in an LQTS family.",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and @GENE$ has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2).",7549550,MYOD1;7857,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,ENG;92,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB p.M170I and @GENE$ p.R408C with SETX p.I2547T and @GENE$ @VARIANT$).,4293318,TAF15;131088,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Using SIFT and PolyPhen, the @VARIANT$ variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in EHMT1 and c.353A > G (p.Asn118Ser) in MFSD8. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (EHMT1 c.1513G > A at a rate of 4.95 x 10-5, @GENE$ @VARIANT$ at a rate of 8.24 x 10-6). As stated above, a heterozygous variant in @GENE$ may not result in developmental regression.",7463850,MFSD8;115814,EHMT1;11698,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,c. 353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"We would like to bring attention to this variant, as we observed a second case of an individual with a severe neurological phenotype and the presence of this rare genetic variant in @GENE$.       3.4. Individuals Carrying Multiple Variants with Evidence Supportive of Pathogenicity We also identified two individuals who carried variants with evidence supportive of pathogenicity in two different genes. A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in EHMT1 and a missense variant c.1777C > G (p.Leu593Val) in SLC9A6. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases. De novo variants in EHMT1 have been reported in individuals with autism, but developmental regression has not been reported. Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.",7463850,SLC9A6;55971,EHMT1;11698,p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,MITF;4892,GJB2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Of the 3 novel variants in DUOX2, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and @VARIANT$ and @VARIANT$ were missense mutations located in the peroxidase-like domain (Fig. S3A).  A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, @GENE$, DUOXA2 and TPO).",7248516,SLC26A4;20132,DUOX2;9689,p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506,p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991,0
"Two of these variants were in genes implicated in heart development and cardiac pathology, @GENE$ and OBSCN (Table 4). The two variants chr18:77170979 G>A for NFATC1 and chr1:@VARIANT$ for @GENE$ lead to novel missense variants, p.R222Q and @VARIANT$ respectively.",5611365,NFATC1;32336,OBSCN;70869,228462101 G>A;tmVar:c|SUB|G|228462101|A;HGVS:c.228462101G>A;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,0
"The cells were transfected with cDNAs of encoding myc-pendrin diease forms with that of @GENE$, and the non-permeable cells were stained with an anti-myc antibody. While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin @VARIANT$, L445W, Q446R, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of @GENE$ (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,EphA2;20929,pendrin;20132,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). The @VARIANT$ (p.His596Arg) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (@VARIANT$), inherited digenically with a homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*).",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,1
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), @GENE$: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the CACNA1C-Q1916R mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of @GENE$-@VARIANT$ mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation.",5426766,SCN5A;22738,CACNA1C;55484,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
(b) A sequence chromatogram showing the @GENE$ (c.253C>T;@VARIANT$) mutation. (c) A sequence chromatogram showing the @GENE$ (@VARIANT$;p.I436V) mutation.,5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"In patient AVM359, one heterozygous VUS (@VARIANT$ [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in @GENE$ were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The patient carried a heterozygous variant of unknown significance in @GENE$, p.(@VARIANT$), defined as likely pathogenic in ClinVar, and a missense variant p.(@VARIANT$) in @GENE$, classified as likely pathogenic.",7224062,PKHD1;16336,PMM2;257,His3124Tyr;tmVar:p|SUB|H|3124|Y;HGVS:p.H3124Y;VariantGroup:17;CorrespondingGene:5314,Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895,1
"(D) SH175-389 harbored a monoallelic p.V193E variant of @GENE$ and a monoallelic p.A194T variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"@GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in @GENE$ were identified (online supplementary table S2).",6161649,SCUBE2;36383,TIMP3;36322,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Among the 8 novel variants, 4 were classified as P (@VARIANT$ and p.K618* in @GENE$, @VARIANT$ in DUOX2) or LP (p.D137E in @GENE$), the other were classified as VUS.",7248516,TSHR;315,DUOX2;9689,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,p.T803fs;tmVar:p|FS|T|803||;HGVS:p.T803fsX;VariantGroup:61;CorrespondingGene:50506,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,1
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively.",8152424,PROKR2;16368,CHD7;19067,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,0
"Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated @GENE$ mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of @GENE$ mutation from hearing loss patients with EVA.",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in @GENE$ and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23.",3125325,USH2A;66151,CDH23;11142,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,1
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (@VARIANT$), @GENE$ (c.607C>T) and C2orf74 (@VARIANT$) genes.",7877624,MITF;4892,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"(C) The EDA mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant EDA allele from his mother; @GENE$ mutations in the parents could not be analyzed. (D) The @GENE$ mutation c.457C>T and WNT10A mutation @VARIANT$ were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis. (E) The EDA mutation c.466C>T and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in EDA and c.511C>T in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,WNT10A;22525,EDA;1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (c.229C>T; @VARIANT$) and d) the @VARIANT$ (p.I80Gfs*13) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Based on the above data and following the ACMG and ACGS variant classification guidelines, we classified the novel @GENE$ @VARIANT$ variant as ""likely pathogenic"" based on three evidences (PM1, PM2, PP3, PP4). However, automated classification software, such as VarSome , assigned a classification of ""variant of unknown significance (VUS) based on two evidences (PM2 and PP3). The @GENE$ @VARIANT$ variant is well described and classified as pathogenic in ClinVar and the Atlas of Cardiac Genetic Variation.",6359299,LAMA4;37604,MYH7;68044,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,SNAI3;8500,TYRO3;4585,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"   Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the GCK gene and in exon 4 (c.872 C > G; @VARIANT$) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the GCK variant was present in the father and the HNF1A variant was present in the mother (Figure 1B). 4. Discussion Monogenic diabetes comprises a group of heterogeneous genetic disorders characterized by the early onset of diabetes, the absence of autoimmunity, and beta-cell dysfunction. Recognition of these forms of diabetes is crucial for reducing both the complications and the treatment costs associated with the disease, and to improve glycemic control with the most appropriate treatment and follow-up for patients. In particular, HNF1A/MODY patients are generally responsive to sulfonylureas, whereas, for GCK/MODY patients, no pharmacological treatment is recommended and diet and regular physical activity are sufficient to maintain good glycemic control. In this case report, we described an unusual molecular diagnosis performed by NGS analysis in a hyperglycemic child, which revealed two distinct genetic variants in the @GENE$ and @GENE$ genes.",8306687,GCK;55440,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (@VARIANT$; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,USH1G;56113,USH2A;66151,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric Cx26/Cx31 connexons. Furthermore, by cotransfection of mCherry-tagged Cx26 and GFP-tagged @GENE$ in human embryonic kidney-293 cells, we demonstrated that the two connexins were able to co-assemble in vitro in the same junction plaque.",2737700,GJB6;4936,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (@VARIANT$; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.",7877624,EDN3;88,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in @GENE$ (DCC)@VARIANT$, and @GENE$ @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,DCC netrin 1 receptor;21081,FGFR1;69065,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,1
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the @GENE$ @VARIANT$ variant in MH. Subject R462 was diagnosed as MHS, which appeared to correlate with @GENE$ @VARIANT$, previously reported in a single MHS subject.",6072915,RYR1;68069,CACNA1S;37257,p.T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0
"The presence of concomitant mutations, such as the TCF3 T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/@GENE$ mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Mutagenesis Sequence variants @GENE$-@VARIANT$ (p.C108Y) and KCNQ1-c.G1748A (@VARIANT$) were introduced into KCNH2 and @GENE$ cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: @VARIANT$, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,CAPN11;21392,c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"This analysis indicated that the CAPN3 variant c.1663G>A (rs138172448), which results in a @VARIANT$ change, and the DES gene variant c.656C>T (rs144901249), which results in a @VARIANT$ change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the @GENE$ and @GENE$ genes, through digenic inheritance, are the cause of the myopathy in this patient.",6180278,CAPN3;52,DES;56469,p.Val555Ile;tmVar:p|SUB|V|555|I;HGVS:p.V555I;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,p.Thr219Ile;tmVar:p|SUB|T|219|I;HGVS:p.T219I;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,1
"Capillary zone electrophoresis was used to obtain the chromatogram of transferrin isoforms in (A) @GENE$ M400I/+ heterozygous; (B) SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; (C,D) SEC23A@VARIANT$/M400I @GENE$R334C/@VARIANT$ double homozygous mutant serum.",4853519,SEC23A;4642,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,0
"Compared with wild-type @GENE$ (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus lead to a reduction of structural stability. However, SCN5A @VARIANT$ showed no significant influence on the RNA structure (Figure 4c,d). The MFE of @GENE$ p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"These findings support the importance of @GENE$ as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYBPC3;215,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation.       Variants in the @GENE$ gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2).",6707335,SQSTM1;31202,KIF5A;55861,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"@GENE$ forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/@GENE$ binding, thus stimulating VEGF signalling (figure 3). The @VARIANT$ (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies.",6161649,SCUBE2;36383,VEGFR2;55639,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered @GENE$ without TES were found to be DFNB7/11, @GENE$, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES.",4998745,DFNB1;2975,DFNB3;56504,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for @GENE$, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for CDH23 , 11%-15% for PCDH15 , and for USH2A in USH2 patients, whereas the implication of VLGR1 and @GENE$ in the latter was minor.",3125325,MYO7A;219,WHRN;18739,c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"  Recently, Gifford et al., identified three missense variants in MKL2 (@VARIANT$), @GENE$ (@VARIANT$), and @GENE$ (Ala119Ser) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MYH7;68044,NKX2-5;1482;4824,Gln670His;tmVar:p|SUB|Q|670|H;HGVS:p.Q670H;VariantGroup:2;CorrespondingGene:57496,Leu387Phe;tmVar:p|SUB|L|387|F;HGVS:p.L387F;VariantGroup:4;CorrespondingGene:4625,0
"A novel variant SCRIB @VARIANT$ (p.K618R) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 @VARIANT$, @GENE$ p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,SCRIB;44228,CELSR1;7665,c.1853A > G;tmVar:c|SUB|A|1853|G;HGVS:c.1853A>G;VariantGroup:2;CorrespondingGene:5754;RS#:139041676;CA#:3816321,p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663,0
"(B) The EDA mutation c.936C>G and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. (C) The EDA mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant EDA allele from his mother; WNT10A mutations in the parents could not be analyzed. (D) The @GENE$ mutation c.457C>T and WNT10A mutation c.637G>A were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis. (E) The EDA mutation @VARIANT$ and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in EDA and @VARIANT$ in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,WNT10A;22525,EDA;1896,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"M1, @GENE$: p.(A179fs*18). M2, CYP1B1: @VARIANT$. M3, CYP1B1: p.(E173*). M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"A novel variant SCRIB c.1853A > G (@VARIANT$) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, @GENE$ p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,0
"We identified four genetic variants (@GENE$-p.R583H, KCNH2-p.C108Y, KCNH2-@VARIANT$, and @GENE$-@VARIANT$) in an LQTS family.",5578023,KCNQ1;85014,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ c.109C>T. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of @VARIANT$ among vertebrates                TOR2A missense variant A TOR2A nonsynonymous SNV (c.568C>T [NM_130459.3], @VARIANT$ [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,REEP4;11888,BSP+;3644,Arg37;tmVar:p|Allele|R|37;VariantGroup:10;CorrespondingGene:80346;RS#:780399718,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.2857A > G @VARIANT$) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G @VARIANT$) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature.",3975370,NOD2;11156,IL10RA;1196,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,p. S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"We did not find a mutation in FGFR1 in any of the individuals carrying a mutation in @GENE$ or @GENE$, either. However, one of the patients heterozygous for the @VARIANT$ mutation in PROKR2 (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in KAL1 exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,PROKR2;16368,PROK2;9268,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0
"These two individuals were heterozygous carriers of p.R1141X mutation in ABCC6 and @VARIANT$ in GGCX. Since heterozygous carriers of @VARIANT$ in @GENE$ alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance. In this case, haploinsufficiency of the carboxylase activity and reduced ABCC6 functions could be complementary or synergistic. The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the ABCC6 gene (p.R1141X) and the GGCX gene (p.S300F) yet did not display any cutaneous findings are not clear. Specifically, while both @GENE$ mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the p.S300F mutation was more pronounced than that of p.V255M.",2900916,ABCC6;55559,GGCX;639,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Therefore, we may speculate that the functional defect of KCNH2-@VARIANT$ could be compromised conductance. Interestingly, it has been reported that the KCNH2-p.C66G variant, located in the PAS domain, reaches the cell surface, but it remains in the immature form and is non-conducting. On the contrary, the functionality of the @GENE$-p.R583H channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. @GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNH2;201,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,gap junction protein beta 3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (@VARIANT$) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, TG, DUOX2, @GENE$, @GENE$, SCL5A5, and IYD, have been detected in numerous cases.",6098846,DUOXA2;57037,SLC26A4;20132,p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0
"Structural changes caused by both the @VARIANT$ and pTrp228Cys variations were not predicted to be disruptive and core GATA4 structure was not altered. Since the changes were in the DNA interaction sites, it is expected that both p.Pro226Leu and p@VARIANT$ mutations could have altered binding and activation of some of GATA4 interaction partners and could also bind to other promoters and potentially change the transcription of several other genes.       In fact, we found segregating genetic variants besides GATA4 in cases 2 and 3 using NGS. In one 46,XY DSD subject without CHD, a heterozygote variant in LRP4 gene was found. Mutations in @GENE$ have been related to the Cenani-Lenz syndactyly syndrome and disruption of canonical WNT/beta-catenin signaling (OMIM 604270), which is not only important in bone formation but also in sexual development.   In our other 46,XY DSD patient without CHD, a heterozygote mutation in LHCGR gene was found together with the GATA4 variant. The same inactivating @GENE$ mutation was previously reported in 46,XY DSD and 46,XX primary amenorrhea.",5893726,LRP4;17964,LHCGR;37276,p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"           Variants in @GENE$ identified in patients with disorders of sex development using massively parallel sequencing. A: A schematic representation of the predicted protein structure of SF1 showing the approximate location of the variants identified in a cohort of DSD patients. The protein domains are as follows: DNA binding domain (DBD) containing two zinc finger motifs (Zn) and the Fushi-tarazu factor 1 box (Ftz-F1), the hinge region and ligand binding domain (LBD). P Box, T-box, A-box, as well as two activational domains:@GENE$, AF2. Patient variants (with patient number denoted by P#) are shown. Five missense mutations were identified in our cohort of 46,XY DSD patients, some of which were recurrent. Two fell within the DBD (p.G35D, @VARIANT$) one in the hinge region (p.G178R), two were in the LBD (@VARIANT$ and p.D364Y).",5765430,SF1;138518,AF1;1482,p.R84H;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681,p.H310D;tmVar:p|SUB|H|310|D;HGVS:p.H310D;VariantGroup:4;CorrespondingGene:6662;RS#:780987236;CA#:8739053,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: @VARIANT$, p.Thr1100Met) and MUTYH (NM_001128425.1: c.536A > G, @VARIANT$) genes, while the other 20 genes could not be clearly linked to cancer predisposition. The identified MSH6 variant was classified as a variant of uncertain significance (VUS) in the Leiden Open Variant Database and the InSiGHT DNA Variant Database. 14 ,  15 The MUTYH variant is the most common pathogenic variant found in the Netherlands. 2                       The digenic inheritance of @GENE$ and @GENE$ variants.",7689793,MSH6;149,MUTYH;8156,c.3299C > T;tmVar:c|SUB|C|3299|T;HGVS:c.3299C>T;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0
"A, The pedigree shows the coinheritance of the monoallelic variants which encode MSH6 p.Thr1100Met and @GENE$ @VARIANT$ in a family affected by colorectal cancer. All spouses were unrelated and unaffected by cancer. Genotypes: @GENE$ @VARIANT$ (T1100M; blue); MUTYH p.Tyr179Cys (Y179C; green); -, wild type.",7689793,MUTYH;8156,MSH6;149,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD.  Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.@VARIANT$ p. S159G) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature.",3975370,IL10RA;1196,IL10RB;523,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,0
"f) Pulmonary function tests of five patients and family two members heterozygous for both the @VARIANT$ and @VARIANT$ variants in @GENE$ and @GENE$, respectively.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,1
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between FLNB and @GENE$. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ TTC26 proteins pulled down the Flag-tagged mutant p.A2282T and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant @VARIANT$ is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that @GENE$ may interact with OFD1.",7279190,TTC26;11786,FLNB;37480,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,TOR2A;25260,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and @GENE$/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,ubiquilin-2;81830,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Subsequently many genes encoding folate pathway enzymes, transporters and receptors have been studied with mostly inconsistent findings.7 More recently, several candidate variants were identified in @GENE$ and GLDC, 2 of the genes constituting the mitochondrial GCS.10, 32 In the present study, we identified a novel missense variant affecting the catalytic domain of the MTHFR gene. This patient additionally carried the @VARIANT$ variant, and a rare missense variant (@VARIANT$) in the @GENE$ gene.",5887939,AMT;409,GLDC;141,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332,1
One IHH patient had compound heterozygous NELF mutations (c.629-21C>G and @VARIANT$); and he did not have mutations in 11 other known IHH/KS genes. Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.629-23G>C;tmVar:c|SUB|G|629-23|C;HGVS:c.629-23G>C;VariantGroup:6;CorrespondingGene:26012;RS#:1474902806,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"A concomitant variant (p.R1193Q, @VARIANT$) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This SCN5A-R1193Q variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).    Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (c.5747A>G, @VARIANT$) in CACNA1C.",5426766,CACNA1C;55484,SCN5A;22738,rs41261344;tmVar:rs41261344;VariantGroup:7;CorrespondingGene:6331;RS#:41261344,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, DUOX2, @GENE$ and TPO).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B).",7248516,SLC26A4;20132,DUOXA2;57037,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Circles, female; squares, male; gray, TNFRSF13B/@GENE$ @VARIANT$ mutation; blue @GENE$ @VARIANT$ mutation (as indicated).",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, @VARIANT$, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A.",3125325,MYO7A;219,USH1C;77476,c.494C>T;tmVar:c|SUB|C|494|T;HGVS:c.494C>T;VariantGroup:185;CorrespondingGene:4647;RS#:111033174;CA#:278676,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"@GENE$ Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (@VARIANT$), and a novel variant, p.W482R of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,rs121908073;tmVar:rs121908073;VariantGroup:11;CorrespondingGene:117531;RS#:121908073,0
"A novel variant SCRIB c.1853A > G (@VARIANT$) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"RNF216 mRNA encoding @VARIANT$ and @GENE$ mRNA encoding @VARIANT$ were less effective in rescuing the phenotypes induced by double-MO injection (Fig. 3, and Fig. S4 in the Supplementary Appendix), suggesting not only that these mutant alleles encode functionally deficient proteins but also that epistatic interactions between these mutations contribute to the disease phenotype in the index pedigree. CLINICAL CHARACTERISTICS OF THE STUDY PATIENTS Patients 1 through 8, who carried variants in @GENE$, had similar clinical histories (Table 1).",3738065,OTUD4;35370,RNF216;19442,R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853,G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858,0
"The presence of concomitant mutations, such as the TCF3 T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of @GENE$/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Most had @GENE$ repeat expansion combined with another mutation (e.g. VCP R155H or @GENE$ @VARIANT$; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in ALS2 and A90V in TARDBP.",5445258,C9orf72;10137,TARDBP;7221,A321V;tmVar:p|SUB|A|321|V;HGVS:p.A321V;VariantGroup:27;CorrespondingGene:23435,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a WDR11 (@VARIANT$;p.I436V) mutation inherited from an unaffected father. Mutant @GENE$ loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.",5505202,WDR11;41229,EMX1;55799,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"These phenomenon indicate that the mutated @GENE$-@VARIANT$ (p.Ala1012Val) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. AGXT2-@VARIANT$ (p.Ala338Val) variant impaired the catabolism of ADMA in EA. hy926 cell lines AGXT2-c.1103C>T (p.Ala338Val) variant was introduced into EA. hy926 cell lines by CRISPR-Cas9 methodology. The conditioned medium was collected at the time point of 24h, 48h and 72h respectively after plant. Elisa analysis showed that the ADMA levels in group harboring a mutated AGXT2-c.1103C were significantly (n=4, P<0.05) higher than the wild-type group (Figure 5), indicating that the enzyme activity of the mutated AGXT2 coding protein was significantly impaired. DISCUSSION In the present study, we established an association between SCAP/@GENE$ mutations with PMI in a digenic pattern.",5725008,SCAP;8160,AGXT2;12887,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the @GENE$ (NM_000179.2: c.3299C > T, @VARIANT$) and @GENE$ (NM_001128425.1: @VARIANT$, p.Tyr179Cys) genes, while the other 20 genes could not be clearly linked to cancer predisposition.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.536A > G;tmVar:c|SUB|A|536|G;HGVS:c.536A>G;VariantGroup:15;CorrespondingGene:4595;RS#:145090475;CA#:7607273,1
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and @GENE$ has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2).",7549550,MYOD1;7857,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,1
"          Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the GGCX and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a @VARIANT$ (p.V255M) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b). This mutation was not present in 100 control alleles by restriction enzyme digestion and/or by direct nucleotide sequencing (Fig. 3c). Secondly, a single nucleotide substitution (c.927C T) resulting in substitution of a serine by phenylalanine in position 300 (p.S300F) was detected (Fig. 3d). Direct sequencing of 150 control alleles detected the S300 codon only, suggesting that this missense substitution is not a frequent polymorphism. Determination of the evolutionary sequence conservation of @GENE$ in different species revealed that the amino acid corresponding to V255 is fully conserved (Fig. 3e).",2900916,VKORC1;11416,GGCX;639,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,valine by methionine at position 255;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,CELSR1;7665,PTK7;43672,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"@GENE$ Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (@VARIANT$), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,rs121908073;tmVar:rs121908073;VariantGroup:11;CorrespondingGene:117531;RS#:121908073,0
"In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,ENG;92,SCUBE2;36383,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"A novel variant @GENE$ c.1853A > G (@VARIANT$) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ p.R769W, DVL3 @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,SCRIB;44228,CELSR1;7665,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Proband 17 inherited @GENE$ p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the CCDC88C @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) @VARIANT$, and the rest were missense variants.",8152424,CHD7;19067,DCC;21081,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"@GENE$-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,GNA14;68386,MRPL15;32210,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and @VARIANT$ variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of @GENE$, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,DVL3;20928,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (c.1514G>A, @VARIANT$). A novel missense mutation was found in @GENE$ (@VARIANT$, p.R133H).",6098846,TG;2430,DUOXA2;57037,p.G505D;tmVar:p|SUB|G|505|D;HGVS:p.G505D;VariantGroup:10;CorrespondingGene:7173;RS#:867829370,c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341,1
"We found that @GENE$-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-@VARIANT$, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD6;2617,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,CDH23;11142,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,KCNE2;71688,LQT2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS7;12395,BBS6;10318,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, @VARIANT$, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.1556G>A;tmVar:c|SUB|G|1556|A;HGVS:c.1556G>A;VariantGroup:9;CorrespondingGene:4647;RS#:111033206;CA#:278629,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"For example, patients 14 and 19 each carried one known truncating mutation (IVS28+1G>T) and a known inactivating mutation (p.R110Q or @VARIANT$). One showed severe CH and low intelligence level, and the other showed mild CH and normal intelligence. Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, @GENE$, @GENE$, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TG;2430,DUOX2;9689,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: @VARIANT$ (p.410T>M), @GENE$: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,1
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 156 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and @GENE$ were found in two or more independent pedigrees.",6081235,MYOD1;7857,MRPL15;32210,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Specifically, heterozygous missense mutations in neighboring residues @VARIANT$ (c.1303G>A;p.A435T; rs318240760) and R448 (c.1343G>A;p.R448Q; rs144440500) have been identified in each of two individuals with idiopathic hypogonadotropic hypogonadism and normosmia. In addition, in a different individual, the @GENE$ p.A435T mutation was identified in association with a mutation in a second gene, @GENE$ (c.275T>C;@VARIANT$; MIM 138850; NM_000406.2), implicating digenic inheritance of this disorder as well.",5505202,WDR11;41229,GNRHR;350,A435;tmVar:c|Allele|A|435;VariantGroup:0;CorrespondingGene:55717;RS#:318240760,p.L92P;tmVar:p|SUB|L|92|P;HGVS:p.L92P;VariantGroup:8;CorrespondingGene:2629;RS#:1141815,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and @GENE$. Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).",7279190,FLNB;37480,TTC26;11786,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,1
" Finally, a subject with the heterozygous @VARIANT$ mutation in @GENE$ (SH60-136) carried a p.D771N variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES. However, neither p.R143W in GJB2 nor @VARIANT$ in @GENE$ was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).",4998745,GJB2;2975,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"Most had @GENE$ repeat expansion combined with another mutation (e.g. VCP R155H or TARDBP @VARIANT$; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in ALS2 and A90V in @GENE$. ALS2 pathogenicity has only been observed in homozygotes, and this individual was heterozygous.",5445258,C9orf72;10137,TARDBP;7221,A321V;tmVar:p|SUB|A|321|V;HGVS:p.A321V;VariantGroup:27;CorrespondingGene:23435,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,GJB2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"@GENE$ mRNA encoding @VARIANT$ and @GENE$ mRNA encoding @VARIANT$ were less effective in rescuing the phenotypes induced by double-MO injection (Fig. 3, and Fig. S4 in the Supplementary Appendix), suggesting not only that these mutant alleles encode functionally deficient proteins but also that epistatic interactions between these mutations contribute to the disease phenotype in the index pedigree.",3738065,RNF216;19442,OTUD4;35370,R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853,G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"We included UTRs to address this lack of knowledge targeting SOD1, TARDBP, FUS, OPTN, VCP and @GENE$, as well as partial coverage in the remaining genes. SKAT analysis revealed a significant excess of rare variants in patients in the UTRs and introns, and inspection of the data suggested that the UTRs contained most of this burden. Previous studies have also suggested this effect (Fig. 1). An Italian study of 420 people with ALS and 480 controls found non-coding mutations in the 3'UTR of FUS in patients, with four unique rare variants in five individuals and no rare variants in controls. Three variants were studied further in primary fibroblast cultures (c.*59G > A, c.*108C > T and @VARIANT$). The UTR variants and a known pathogenic exonic FUS variant all cause a mislocalization of the FUS protein, an effect not seen in the other patients or controls. Similarly, the @VARIANT$ variant, found in two subjects with a rapidly progressive form of ALS, increase @GENE$ expression dramatically; overexpression of wild-type FUS causes an ALS-like syndrome in mice.",5445258,UBQLN2;81830,FUS;134091,c.*110G > A;tmVar:c|SUB|G|*110|A;HGVS:c.*110G>A;VariantGroup:62;CorrespondingGene:2521,c.*48G > A;tmVar:c|SUB|G|*48|A;HGVS:c.*48G>A;VariantGroup:59;CorrespondingGene:6647,0
"M1, CYP1B1: @VARIANT$. M2, CYP1B1: p.(E387K). M3, @GENE$: p.(E173*). M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(A179fs*18);tmVar:p|FS|A|179||18;HGVS:p.A179fsX18;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"In this Hungarian cohort, we identified two patients (1.9%) with @GENE$ variants (L106V and R572W). The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age.",6707335,CCNF;1335,ALS2;23264,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"Indeed the @VARIANT$ interacts with other residues in the @GENE$, EC3, the third transmembrane domain (TM3), and the TM; thus, its deletion could reduce the @GENE$ protein stability (Figure 2). The genetic investigation of the mother of HH12 showed that she was a carrier of the same likely pathogenic mutation [p.(Lys205del)] at a heterozygous state. Phyre2 prediction of the deleterious effect of @VARIANT$ on the 3D protein structure.",8446458,EC2;37943,PROKR2;16368,lysine amino acid at position 205;tmVar:|Allele|LYSINEAMINO|205;VariantGroup:11;CorrespondingGene:6939,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 @VARIANT$ to immunoprecipitate HA-@GENE$ E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and @GENE$ proteins to associate with wild-type CYP1B1 and TEK, respectively.",5953556,TEK;397,CYP1B1;68035,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Both of which suggest that wild-type splicing would be affected     A recent study (Mazen et al., 2016) identified pathogenic variants in NR5A1 and @GENE$ in an individual with 46,XY gonadal dysgenesis, highlighting the possibility that digenic inheritance may play a role in the large phenotypic spectrum associated with @GENE$ variants. We also identified two patients with multiple affected diagnostic DSD genes (Table 3). Patient 3 was found to harbor a previously reported @VARIANT$ variant in NR5A1, alongside a rare variant in ZFPM2 (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3).",5765430,MAP3K1;8056,NR5A1;3638,p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ p.M170I and TAF15 @VARIANT$ with SETX p.I2547T and @GENE$ @VARIANT$).,4293318,VAPB;36163,SETX;41003,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and TNFRSF13B/@GENE$ @VARIANT$ mutations.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,1
"There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0
"This mutation changes codon 554 from arginine to a stop codon (@VARIANT$; p.Arg554Stop) and has been previously reported. The mother did not carry this luteinizing hormone/choriogonadotropin receptor (LHCGR) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, @GENE$, and @GENE$ promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants @VARIANT$ and Pro226Leu activated the CYP17 promoter similar to wt.",5893726,SRY;48168,CYP17;73875,c.1160C>T;tmVar:c|SUB|C|1160|T;HGVS:c.1160C>T;VariantGroup:1;CorrespondingGene:2626;RS#:368991748;CA#:172121374,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"    Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Her mother with c.1339 + 3A>T in @GENE$ and her father with a missense mutation @VARIANT$ in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A4;20071,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (p.R559W) and @GENE$: c.7942G > A (@VARIANT$), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,p.G2648S;tmVar:p|SUB|G|2648|S;HGVS:p.G2648S;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,1
"These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in @GENE$ play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and MYBPC3 (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in @GENE$ (Asp955Asn) and TNNT2 (@VARIANT$), both sarcomeric genes.",6359299,LAMA4;37604,MYH7;68044,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0
Three families were heterozygous for a previously reported single-nucleotide @GENE$ deletion (@VARIANT$/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (c.1559G>A/@VARIANT$) that cosegregated with both the AI phenotype and the ENAM mutation.,6785452,ENAM;9698,LAMA3;18279,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,1
"Whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach was performed and a novel single nucleotide deletion mutation (@VARIANT$) in the @GENE$ gene and a rare heterozygous, missense damaging variant (c.101T>G; @VARIANT$) in the @GENE$ was identified.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,1
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
"Interestingly, four of these @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,1
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1;68136,DUOX1 and -2;53905;50506,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,MAP4K4;7442,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, @VARIANT$, p.S82T, p. A85P, @VARIANT$, p.F112S, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,FOXC1;20373,PITX2;55454,p.P79T;tmVar:p|SUB|P|79|T;HGVS:p.P79T;VariantGroup:108;CorrespondingGene:6012,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,0
"18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by @GENE$. 20  The identified CUX1 (NM_001202543: c.1438A > G, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and @GENE$. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: @VARIANT$, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,OGG1;1909,CAPN9;38208,c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"One patient had a novel de novo variant of @GENE$ (@VARIANT$, p. Ser509fs) and a hot spot variant of @GENE$ (@VARIANT$, p. Trp178Ser) simultaneously.",8796337,KAl1;55445,PROKR2;16368,c.1524delA;tmVar:c|DEL|1524|A;HGVS:c.1524delA;VariantGroup:17;CorrespondingGene:3730,c.533G > C;tmVar:c|SUB|G|533|C;HGVS:c.533G>C;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$).",5887939,PRICKLE4;22752,DVL3;20928,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"Sequence alterations were detected in the @GENE$ (rs144651558), RYR1 (rs143445685), CAPN3 (@VARIANT$), and @GENE$ (@VARIANT$) genes.",6180278,COL6A3;37917,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous @GENE$ mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"A novel missense mutation was found in @GENE$ (c.398G>A, @VARIANT$). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, @VARIANT$ and p.S1067L, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001).",6098846,DUOXA2;57037,DUOX2;9689,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,p.H678R;tmVar:p|SUB|H|678|R;HGVS:p.H678R;VariantGroup:21;CorrespondingGene:50506;RS#:57659670;CA#:7538401,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,UBQLN2;81830,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CAPN11;21392,SPTBN4;11879,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD1;20750,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,0
"The other two LRP6 variants, c.2450C>G (p.Ser817Cys) and @VARIANT$ (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the WNT10A mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance. Segregation analysis of the parent-child trio revealed that the father, who was hypodontic, carried all three LRP6 variants but not the WNT10A mutation, which was found in the mother. This segregation pattern of mutations suggested a plausible synergetic effect from the @GENE$ and @GENE$ mutations, which caused thirteen missing teeth in the proband.",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and TAF15 @VARIANT$ with SETX p.I2547T and SETX p.T14I).",4293318,SOD1;392,ANG;74385,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,CAPN11;21392,MYOD1;7857,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"        Molecular Data All three probands carry two heterozygous variants: SQSTM1, c.1175C>T (p.Pro392Leu), and TIA1, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and SQSTM1 variants have been reported in multiple databases. The @GENE$ variant is designated as @VARIANT$ in dbSNP and reported at allele frequencies of 0.0009 in the Exome Aggregation Consortium database (ExAC), 0.0024 in 1,000 Genomes Project database (TGP), and 0.0015 in the NHLBI GO Exome Sequencing Project (GO-ESP) (accessed January 23, 2018) and is more frequent in certain European populations.",5868303,TIA1;20692,SQSTM1;31202,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,rs104893941;tmVar:rs104893941;VariantGroup:1;CorrespondingGene:8878;RS#:104893941,0
"        Molecular Data All three probands carry two heterozygous variants: @GENE$, c.1175C>T (@VARIANT$), and @GENE$, @VARIANT$ (p.Asn357Ser).",5868303,SQSTM1;31202,TIA1;20692,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 3;7338,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of USH2A (NM_007123), R5143C, C4870F, and @VARIANT$ with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and Ankyrin 1 (@GENE$) identified in SH 94-208).",4998745,USH2A;66151,ANK1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,G805A;tmVar:c|SUB|G|805|A;HGVS:c.805G>A;VariantGroup:14;CorrespondingGene:7399;RS#:587783023;CA#:270788,0
Merged images showing pro-COL1A1 colocalization with @GENE$ in wild-type (Wt) (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ MAN1B1R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ @GENE$R334C/@VARIANT$ double homozygous (L) fibroblasts.,4853519,PDI;55495,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"The in-frame insertion variant @VARIANT$ (@VARIANT$) in @GENE$ was identified in CS63. The patient was a 6-year-old female with complaints of restricted neck motion and torticollis. Radiological evaluation detected fusion of the cervical vertebrae at C6-T1, scoliosis, diastematomyelia, syringomyelia, and polycystic kidney disease. BAZ1B encodes a member of a bromodomain protein family that is involved in chromatin-dependent regulation of transcription. Deletion of this gene has been reported in Williams-Beuren syndrome (@GENE$), a developmental disorder featuring multiple skeletal deformities such as scoliosis, hallux valgus, little-finger clinodactyly, fusion of the cervical spine and Chiari I malformation.",7149842,BAZ1B;22651,WBS;2006,c.3804_3821dupGGAGGAGGAGGAAGAAGA;tmVar:c|DUP|3804_3821|GGAGGAGGAGGAAGAAGA|;HGVS:c.3804_3821dupGGAGGAGGAGGAAGAAGA;VariantGroup:32;CorrespondingGene:9031,"p. Glu1268_Glu1273dup;tmVar:p|DUP|1268,1273|E|;HGVS:p.1268,1273dupE;VariantGroup:40;CorrespondingGene:23426",0
"20  The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: @VARIANT$, p.Glu274Asp) and the @GENE$ (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,TRIP6;37757,CAPN9;38208,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling.",6161649,MAP4K4;7442,BMP;55955,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In our study, we identified four genetic variants in three genes (KCNQ1-p.R583H, KCNH2-@VARIANT$, @GENE$-p.K897T, and @GENE$-@VARIANT$).",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Our study suggests that the @GENE$-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"(A) The @GENE$ mutation @VARIANT$ and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the @GENE$ [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:@VARIANT$; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).,6053831,PCDH15;23401,USH1G;56113,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,c.1093G > A;tmVar:c|SUB|G|1093|A;HGVS:c.1093G>A;VariantGroup:1;CorrespondingGene:124590;RS#:538983393;CA#:8753931,1
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,CDON;22996,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"    Results We identified the digenic heterozygous mutations of KCNH2 p.307_308del (NM_001204798, c.921_923del) and @GENE$ @VARIANT$ (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. Subsequently, she occurred with obvious sinus arrest with persistent ventricular pacing of implantable cardioverter-defibrillator. The heterozygous SCN5Ap.R1865H was carried by her father and sister but not carried by I:2. II:1 carried with KCNH2 p.307_308del as a de novo mutation, but not existed in other family members. RNA secondary structure of @GENE$ @VARIANT$ showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in MYO7A and @GENE$, and, all the more, the mutations in the three genes (Figure 2).",3125325,CDH23;11142,USH1G;56113,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"The female @GENE$-@VARIANT$ mutation carriers with @GENE$-@VARIANT$ variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the CACNA1C-Q1916R mutation (IV-4) showed the ER ECG pattern.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,1
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [p.Leu104Pro]) in @GENE$ were identified (online supplementary table S2).",6161649,VEGFR2;55639,TIMP3;36322,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,0
"The mother carried the MYH7 @VARIANT$ mutation and had mild DCM at age 27. The father carried the LAMA4 @VARIANT$ variant and did not have echocardiographic manifestations of DCM at age 29. The proband phenotype was severe infantile DCM. These observations highlight the importance of genetic and echocardiographic screening of family members of patients with DCM. DCM is a genetically heterogeneous condition, associated with different genes including those with gene products involved in cytoskeletal, nucleoskeletal, mitochondrial, and calcium pathways. Many reported mutations in these pathways are rare variants that are unique to specific families. The most frequent DCM-associated gene is TTN, mutated in 18% and 25% of sporadic and familial DCM cases, respectively compared to mutations in @GENE$ and @GENE$ accounting for 83% of HCM cases.",6359299,MYH7;68044,MYBPC3;215,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,0
"Importantly, when we sorted these 10 remaining variants by pathogenicity score based on CADD_Phred score, all 4 @GENE$ variants and the OPTN variant had scores higher than 20, meaning that those substitutions are predicted to be among the 1% most deleterious substitutions in the human genome (Table 1; Figure 1a). Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:@VARIANT$; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,TBK1;22742,OPTN;11085,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,0
"However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and @GENE$ and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated @GENE$ mutation (@VARIANT$; p.T468M) and a novel, potentially pathogenic missense SOS1 variant (@VARIANT$; p.P340S) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,neurofibromatosis 1;226,PTPN11;2122,c.1403 C > T;tmVar:c|SUB|C|1403|T;HGVS:c.1403C>T;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,c.1018 C > T;tmVar:c|SUB|C|1018|T;HGVS:c.1018C>T;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0
"However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) p. Thr584Serfs*5, and the rest were missense variants. However, the possibility of being loss-of-function intolerant (pLI) value of IGSF10 is zero, which means that single heterozygous LoF variant of IGSF10 is not sufficient to cause disease. Furthermore, proband @GENE$ was only detected one heterozygous variant, PROKR2 @VARIANT$, whereas probands P12 and P14 carried the same PROKR2 variant and additional variants in other candidate genes.",8152424,CCDC88C;18903,P18;100689229,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Trp178Ser;tmVar:p|SUB|W|178|S;HGVS:p.W178S;VariantGroup:0;CorrespondingGene:128674;RS#:201835496;CA#:270917,0
"We found that @GENE$-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel @GENE$-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNH2;201,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Capillary zone electrophoresis was used to obtain the chromatogram of transferrin isoforms in (A) @GENE$ M400I/+ heterozygous; (B) SEC23AM400I/+ @GENE$R334C/+ double heterozygous; (C,D) SEC23A@VARIANT$/M400I MAN1B1R334C/@VARIANT$ double homozygous mutant serum.",4853519,SEC23A;4642,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6.",6610752,KCNH2;201,KCNE2;71688,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with @GENE$ mutation.",7877624,SNAI3;8500,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and KCNQ1-@VARIANT$ (p.R583H) were introduced into @GENE$ and @GENE$ cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,1
Both sisters inherited the @GENE$ gene mutation R127W from their mother and the @GENE$ gene mutation P291fsinsC (@VARIANT$) from their father. The father was diagnosed with diabetes at 45 years of age. Their brother is heterozygous for the HNF4A @VARIANT$ mutation.,4090307,HNF4A;395,HNF1A;459,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
"R85C in @GENE$ (MIM 607123; NM_144773.2; @VARIANT$) inherited from an unaffected mother and c.1306A>G;p.I436V in @GENE$ (MIM 606417; NM_018117.11; @VARIANT$) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1).",5505202,PROKR2;16368,WDR11;41229,rs141090506;tmVar:rs141090506;VariantGroup:1;CorrespondingGene:128674;RS#:141090506,rs34602786;tmVar:rs34602786;VariantGroup:3;CorrespondingGene:55717;RS#:34602786,1
"Two variants, likely pathogenic @VARIANT$ and pathogenic @VARIANT$, in HMBS were found in two subjects. Pathogenic variants in HMBS are associated with Acute Intermittent Porphyria. We consider HMBS variants as incidental findings that are likely unrelated to phenotype. Variant segregation in subjects All subjects were heterozygous carriers of pathogenic or deleterious variants in genes known to affect various enzymatic pathways of cellular energy. Five subjects (R279, R410, R465, R469 and R470) carried pathogenic and deleterious variants in genes known to affect glycogen metabolism (GBE1, PYGM), FAO (@GENE$ and @GENE$), fatty acid and amino acid catabolism (PCCB), oxidative phosphorylation (ELAC2, NDUFA6, NDUFA10 and NUBPL), mitochondrial matrix enzymes (OAT and TIMM50).",6072915,ACADVL;5,CPT2;77,p. R175W;tmVar:p|SUB|R|175|W;HGVS:p.R175W;VariantGroup:4;CorrespondingGene:5256;RS#:376233279;CA#:10361894,p. R225Q;tmVar:p|SUB|R|225|Q;HGVS:p.R225Q;VariantGroup:11;CorrespondingGene:779,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and p.A481V missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the @VARIANT$ mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain.",4470809,TANK-binding kinase 1;22742,OPTN;11085,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors.",3842385,EDA;1896,WNT10A;22525,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"    Naive B cells isolated from the brother with the homozygous @GENE$/TACI @VARIANT$ mutation (II.4) were able to produce detectable IgG in vitro via the T-cell-independent pathway (Figure 4a). However, his (II.4) cells produced consistently lower levels of IgG compared to his healthy niece (III.2). Previous studies have shown TNFRSF13B/TACI C104R homozygous individuals are able to produce some IgG in vitro with APRIL stimulation alone. This is likely to be augmented by Toll-like receptor signalling with CpG as well as IL-4 and IL-21, in our experiments. As expected, his cells produce greater amounts of IgG through his intact T-cell-dependent pathway. The proband's son (III.1) carrying only the heterozygous @GENE$ @VARIANT$ mutation is also able to produce some IgG in vitro via activation of both pathways, but at much lower levels than his wild-type sister (III.2).",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1
"There is thus strong support from human, murine and equine studies for the pathogenicity of the @GENE$ @VARIANT$ mutation in our family. Our study also offers new insights into the role of @GENE$/TACI mutations in the pathogenesis of CVID. The @VARIANT$ mutant is a low frequency variant in population databases (0.32% in Exome Aggregation Consortium) and although earlier publications considered this variant to be disease-causing and expressed in up to 10% of CVID patient cohorts, it, and other TNFRSF13B/TACI variants were subsequently found to be present in ~2% of healthy control populations.",5671988,TCF3;100147220,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$).",6610752,KCNH2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, @VARIANT$), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. @GENE$ gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of @GENE$ and SCN5A genes are closely related to LQTS. The mutations of KCNH2 @VARIANT$ and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,SCN5A;22738,KCNH2;201,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"These two individuals were heterozygous carriers of @VARIANT$ mutation in @GENE$ and @VARIANT$ in GGCX. Since heterozygous carriers of p.R1141X in ABCC6 alone do not manifest PXE and @GENE$ mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 @VARIANT$ and SCRIB c.3979G>A). One patient (f93-80) had a novel @GENE$ missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PTK7;43672,FZD6;2617,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes.     ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90.",3842385,EDA;1896,WNT10A;22525,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Therefore, in this study, SCN5A @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and @GENE$ p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 @VARIANT$ may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in @GENE$ gene and a homozygous splice-donor mutation (@VARIANT$) in CARD9 gene. (D) Western Blot of @GENE$ and MYD88 proteins performed on PBMC, EBVB, and PHA derived T cell lines.",6383679,MYD88;1849,CARD9;14150,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.@VARIANT$, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$, p.R50C).",7279190,FLNB;37480,TTC26;11786,R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260,1
"    Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and WNT10A mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,VPS13C;41188,MRPL15;32210,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"No mutations in @GENE$, TPO, or @GENE$ gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: @VARIANT$ (p.Y138X) in one patient.",6098846,SLC5A5;37311,IYD;12352,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"A rare variant in @GENE$, c.428C>T; @VARIANT$, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported @GENE$/FOG2 (@VARIANT$; p.Met544Ile) pathogenic missense alteration was identified.",7696449,AMH;68060,ZFPM2;8008,p.Thr143Ile;tmVar:p|SUB|T|143|I;HGVS:p.T143I;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,c.1632G>A;tmVar:c|SUB|G|1632|A;HGVS:c.1632G>A;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Moller et al. reported an index case with digenic variants in MYH7 (L1038P) and MYBPC3 (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and TNNT2 (@VARIANT$), both sarcomeric genes. Here we reported heterozygous variants in genes that play roles in two different cardiomyocyte components; MYH7:part of the sarcomere, and LAMA4:part of the ECM/signalling component. To our knowledge, this is the first description of digenic mutations in @GENE$ and @GENE$. The mutations were inherited from the parents, the mother carrying a MYH7 mutation and with mild DCM, and a father carrying the LAMA4 variation but with a normal heart at age 29.",6359299,MYH7;68044,LAMA4;37604,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,ubiquilin-2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a @GENE$ (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father.",5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Therefore, we may speculate that the functional defect of @GENE$-@VARIANT$ could be compromised conductance. Interestingly, it has been reported that the KCNH2-p.C66G variant, located in the PAS domain, reaches the cell surface, but it remains in the immature form and is non-conducting. On the contrary, the functionality of the @GENE$-@VARIANT$ channels was not severely compromised in a manner typical of LQTS-associated mutations.",5578023,KCNH2;201,KCNQ1;85014,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"Biallelic pathogenic variants in the @GENE$ gene may lead to MKS3, with overlapping symptoms to ADPKD, including renal cysts and central nervous dysplasia, among which the latter was not evidently manifested in Family 24. One possible explanation for this could be that @VARIANT$ (p.R213C) was possibly a hypomorphic variant. 47  The @GENE$ gene is expressed in a subset of embryonic tissues 48  and is involved in cilia formation. This gene was designated as the causative gene for MKS13. 49  The proband foetus with typical MKS13 phenotypes in Family 25 carried two novel TMEM107 variants: c.129delC (@VARIANT$) and c.64_66delGTC (p.V22del), both of which were predicted with large fragment truncation and were expected to cause a functional defect.",8256360,TMEM67;71886,TMEM107;12052,c.637C > T;tmVar:c|SUB|C|637|T;HGVS:c.637C>T;VariantGroup:3;CorrespondingGene:5314;RS#:866575098;CA#:138924774,p.E44Rfs*98;tmVar:p|FS|E|44|R|98;HGVS:p.E44RfsX98;VariantGroup:7;CorrespondingGene:84314;RS#:745751675;CA#:8371043,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The female @GENE$-Q1916R mutation carriers with @GENE$-@VARIANT$ variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the CACNA1C-@VARIANT$ mutation (IV-4) showed the ER ECG pattern.",5426766,CACNA1C;55484,SCN5A;22738,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the @GENE$/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (FZD6 @VARIANT$ and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR2;1078,FAT4;14377,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,0
"This study provides additional evidence that @GENE$ missense variants may contribute to the development of sALS.    Missense variants in the @GENE$ gene were detected in four patients: the @VARIANT$ variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients.",6707335,NEK1;14376,NEFH;40755,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0
"Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(Ser872Gly) variant in @GENE$, while only one fetus inherited the p.(Arg872Gly) @GENE$ variant. The analysis of PKHD1 performed on the first fetus showed no mutations. We suggest that: 1) the PKD2 p.(@VARIANT$) variant is pathogenic, since it is de-novo in a patient with a renal cystic disease and is transmitted to both fetuses; 2) the p.(@VARIANT$) variant in PKD1 is hypomorphic, since it does not cause renal disease in the father (age 44 years), but worsens the renal phenotype when co-inherited with a PKD2 mutation; 3) the missense variant p.(Arg872Gly) in PKD2, already described as disease-causing in HGMD database (Neumann et al.,), is likely benign, since it is present in a healthy man and does not segregate with disease in the fetuses.",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ @VARIANT$), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A).",5887939,PRICKLE4;22752,DVL3;20928,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,SOX10;5055,MITF;4892,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Four genes (including @GENE$, ZFHX3, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only @GENE$-@VARIANT$ (p.Ala1012Val) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,AGXT2;12887,SCAP;8160,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, @GENE$, DCC, PROP1, PLXNA1, and @GENE$ genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant p.(Lys205del). The DUSP6 gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of PROKR2 were extracted, which revealed one common variant (@VARIANT$) in intron 1 with a MAF of 0.3 according to GnomAD.",8446458,ANOS1;55445,SEMA7A;2678,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,c.-9 + 342A > G;tmVar:c|SUB|A|-9+342|G;HGVS:c.-9+342A>G;VariantGroup:3;CorrespondingGene:128674;RS#:7351709,0
The PITX2 variant @VARIANT$ did not show significant protein stability differences with the wild-type protein (Fig 6C and Fig 6D). @GENE$ @VARIANT$ variant decreases protein stability. Time course stability analysis of FOXC2 (A) and @GENE$ (C) coding variants found in PCG patients was carried out by transient expression in HEK-293T cells.,6338360,FOXC2;21091,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.H395N;tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT5;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin @VARIANT$, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant @VARIANT$. The @GENE$ gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,DUSP6;55621,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"  Genetic analysis of  @GENE$   Only three out of 82 individuals were found to have heterozygous variants in ECHDC1. Individual P1 and P3 carried the c.389T>C (@VARIANT$) and the c.221-4_222delinsTA ECHDC1 variant, respectively and were homozygous for @GENE$ @VARIANT$ with urinary EMA >40 mmol/mol creatinine (Group B, see Materials and Methods).",8518634,ECHDC1;23106,ACADS;20057,p.Met130Thr;tmVar:p|SUB|M|130|T;HGVS:p.M130T;VariantGroup:2;CorrespondingGene:55862;RS#:368710940,c.625G>A;tmVar:c|SUB|G|625|A;HGVS:c.625G>A;VariantGroup:1;CorrespondingGene:35;RS#:1799958;CA#:145599,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"                              In the patient with the monoallelic mutation in exon 1 (@VARIANT$), additional studies were carried out to search for further genetic defects. A PCR amplicon containing GNRHR exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (rs373270328), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (@VARIANT$;[=]) (p.Arg80Cys) in the @GENE$ gene.         The @GENE$ frameshift mutation was identified in two different families and has not been reported before.",5527354,PROKR2;16368,GNRHR;350,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,c.[238C > T];tmVar:c|SUB|C|238|T;HGVS:c.238C>T;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, @VARIANT$) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous SCN5A @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,SCN5A;22738,KCNH2;201,c.A3083T;tmVar:c|SUB|A|3083|T;HGVS:c.3083A>T;VariantGroup:5;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, DVL3 p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, @GENE$ p.R1057C and @GENE$ p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,CELSR1;7665,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited @GENE$ @VARIANT$ and @GENE$/TACI C104R mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing @GENE$/TGF-beta signalling.",6161649,ENG;92,BMP;55955,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB @VARIANT$ and @GENE$ p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,SOD1;392,TAF15;131088,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"(A) Segregation of the @GENE$-p.R583H, KCNH2-@VARIANT$, @GENE$-p.K897T, and KCNE1-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"However, it was hard to determine whether the coexisting interactions of @GENE$ @VARIANT$ and @GENE$ @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,gap junction protein beta 3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, @VARIANT$ and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.3719G>A;tmVar:c|SUB|G|3719|A;HGVS:c.3719G>A;VariantGroup:87;CorrespondingGene:4647;RS#:542400234;CA#:5545997,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); @GENE$-@VARIANT$ and COL4A5-@VARIANT$. Mutations in @GENE$ cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis.",5954460,LAMA5;4060,COL4A5;133559,p.Pro1243Leu;tmVar:p|SUB|P|1243|L;HGVS:p.P1243L;VariantGroup:2;CorrespondingGene:3911;RS#:756101090;CA#:9942875,p.Asp654Tyr;tmVar:p|SUB|D|654|Y;HGVS:p.D654Y;VariantGroup:4;CorrespondingGene:1287;RS#:1131692060,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,1
"We report digenic variants in SCRIB and @GENE$ associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,CELSR1;7665,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of @GENE$, @VARIANT$ was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of @GENE$, and @VARIANT$ was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,CELSR1;7665,SCRIB;44228,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (CSF1R), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (FUS).       CNV analysis of the 21 neurodegenerative disease genes using Ingenuity Variant Analysis software further identified one patient with a partial deletion of OPTN (NM_001008211.1:c.1243-740_1612+1292delins25; @VARIANT$).",4470809,OPTN;11085,TBK1;22742,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,"p.Gly538Glufs27;tmVar:p|SUB|G|538,27|E;HGVS:p.G538,27E;VariantGroup:33;CorrespondingGene:10133",0
"Of the 3 novel variants in DUOX2, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and @VARIANT$ and @VARIANT$ were missense mutations located in the peroxidase-like domain (Fig. S3A).  A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, @GENE$, @GENE$ and TPO).",7248516,DUOX2;9689,DUOXA2;57037,p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506,p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991,0
"The presence of concomitant mutations, such as the TCF3 @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/@GENE$ mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and @GENE$ mutations. KCNH2 @VARIANT$ and @GENE$ @VARIANT$ of the proband were validated as positive by Sanger sequencing.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Mutations in NRXN1 and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN2;86984,NRXN1;21005,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (@VARIANT$)::CYP1B1 (@VARIANT$), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of TEK to respond to ligand stimulation, indicating perturbed TEK signaling. Overall, our data suggest that interaction of TEK and CYP1B1 contributes to PCG pathogenesis and argue that @GENE$-CYP1B1 may perform overlapping as well as distinct functions in manifesting the disease etiology.",5953556,CYP1B1;68035,TEK;397,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"The genotypes of SLC20A2 (NM_001257180.2: @VARIANT$, p.His596Arg) and @GENE$ (NM_002609.4: @VARIANT$, p.Arg106Pro) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding PDGFRB, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Two unaffected subjects, SH60-137 and SH60-139, also carried p.D771N in @GENE$. This indicates that neither @VARIANT$ in @GENE$ nor @VARIANT$ in WFS1 contributed to SNHL in SH60-136 and that p.R143W in GJB2 was an incidentally detected variant in this subject.",4998745,WFS1;4380,GJB2;2975,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Two novel variants were identified in @GENE$, including one frameshift mutation (@VARIANT$, p.C687LfsX34) and one missense mutation (@VARIANT$, p.G505D). A novel missense mutation was found in @GENE$ (c.398G>A, p.R133H).",6098846,TG;2430,DUOXA2;57037,c.2060_2060delG;tmVar:c|DEL|2060_2060|G;HGVS:c.2060_2060delG;VariantGroup:68;CorrespondingGene:405753,c.1514G>A;tmVar:c|SUB|G|1514|A;HGVS:c.1514G>A;VariantGroup:10;CorrespondingGene:6528;RS#:867829370,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"We observed that recombinant @GENE$ and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (@VARIANT$), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"On the other hand, when the CCDC141 variant was at a heterozygous state, prediction by ORVAL yielded only two pathogenic digenic combinations with @GENE$ and @GENE$ variants in HH1F and HH1P cases (Figure 4). The variant pair CCDC141 (@VARIANT$)-PROKR2 (@VARIANT$) was classified by ORVAL as true digenic.",8446458,PROKR2;16368,DUSP6;55621,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,c.868C > T;tmVar:c|SUB|C|868|T;HGVS:c.868C>T;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257,0
The @GENE$ gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).,8446458,DUSP6;55621,SEMA7A;2678,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,1
"In AS patient IID27, the two mutations in @GENE$ and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation c.1339 + 3A>T in COL4A5, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A4;20071,p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,1
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,1
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The @GENE$ @VARIANT$ mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous @GENE$ p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of @GENE$ (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .   In vitro evaluation of a similarly truncated DUOX1 isoenzyme comprising amino acids 1 to 593 alone abolished H2O2-generating activity. Moreover, similar truncations in the highly homologous @GENE$ [p.Q686*, p.R701*, @VARIANT$;(IVS19-2A>C), p.S965fsX994] are associated with CH or severely impaired H2O2-generating activity in vitro.",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p.(G418fsX482);tmVar:p|FS|G|418||482;HGVS:p.G418fsX482;VariantGroup:2;CorrespondingGene:50506,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare @GENE$ missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 @VARIANT$), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PTK7;43672,CELSR2;1078,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0
"These seven amino acids are located in the peroxidase- (PO-) like domain and are conserved among @GENE$ orthologs (Figure 2 and Figure S1). The latter variant likely resulted in aberrant splicing of the transcript. Two novel variants were identified in @GENE$, including one frameshift mutation (@VARIANT$, p.C687LfsX34) and one missense mutation (c.1514G>A, @VARIANT$).",6098846,DUOX2;9689,TG;2430,c.2060_2060delG;tmVar:c|DEL|2060_2060|G;HGVS:c.2060_2060delG;VariantGroup:68;CorrespondingGene:405753,p.G505D;tmVar:p|SUB|G|505|D;HGVS:p.G505D;VariantGroup:10;CorrespondingGene:7173;RS#:867829370,0
"Sequence alterations were detected in the COL6A3 (rs144651558), @GENE$ (rs143445685), @GENE$ (@VARIANT$), and DES (@VARIANT$) genes.",6180278,RYR1;68069,CAPN3;52,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"M2, @GENE$: p.(E387K). M3, CYP1B1: p.(E173*). M4, @GENE$: @VARIANT$. M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Moderate iodine deficiency in association with double heterozygosity for @GENE$ and @GENE$ mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1;68136,DUOX2;9689,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and @GENE$ @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,CELSR1;7665,SCRIB;44228,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and @GENE$ @VARIANT$ with @GENE$ p.I2547T and SETX p.T14I).,4293318,TAF15;131088,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
Both sisters inherited the @GENE$ gene mutation @VARIANT$ from their mother and the @GENE$ gene mutation P291fsinsC (@VARIANT$) from their father.,4090307,HNF4A;395,HNF1A;459,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,1
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"For Case 1, a novel missense VUS (variant of unknown significance) variant (@VARIANT$; p.Arg121Trp) in the @GENE$ gene was identified in the patient and his father. A rare variant in @GENE$, @VARIANT$; p.Thr143Ile, was detected in Case 2 and was classified as VUS.",7696449,STAR;297,AMH;68060,c.361C>T;tmVar:c|SUB|C|361|T;HGVS:c.361C>T;VariantGroup:7;CorrespondingGene:6770;RS#:34908868;CA#:4715265,c.428C>T;tmVar:c|SUB|C|428|T;HGVS:c.428C>T;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25  The contribution of the genetic variants, other than @GENE$ and MUTYH, to cancer risk cannot be completely excluded.",7689793,TRIP6;37757,MSH6;149,c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"The genotypes of SLC20A2 (NM_001257180.2: @VARIANT$, p.His596Arg) and PDGFRB (NM_002609.4: @VARIANT$, p.Arg106Pro) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding @GENE$, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"                                    Tumor analysis MMR deficiency in tumor samples was assessed by microsatellite instability analysis and immunohistochemical detection of the four MMR proteins (MLH1, MSH2, @GENE$, and @GENE$). 11  KRAS codon 12/13 mutations were screened with Sanger sequencing. 12   Functional MMR assay In vitro MMR activity assay was performed as previously described. 13   RESULTS We performed germline whole-exome sequencing on three CRC patients diagnosed before 60 years of age (III-1, III-7, III-8, Figure 1A) and who belonged to a CRC family comprising of seven cancer patients divided over two generations. Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: c.3299C > T, @VARIANT$) and MUTYH (NM_001128425.1: @VARIANT$, p.Tyr179Cys) genes, while the other 20 genes could not be clearly linked to cancer predisposition.",7689793,MSH6;149,PMS2;133560,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.536A > G;tmVar:c|SUB|A|536|G;HGVS:c.536A>G;VariantGroup:15;CorrespondingGene:4595;RS#:145090475;CA#:7607273,0
" @GENE$ and TTC26 variants in individuals with AIS. (A) Profiles of rare damaging variants in FLNB. Rare variants are represented by lollipops and counts of alleles with variants in cases (top panel) and controls (bottom panel) are shown. (B, C) Local view of in silico structure analysis for the WT and mutant FLNB structures (B, variant R566L; C, variant A2282T). The WT structure of FLNB is shown in purple, and the mutant structure of FLNB is shown in green. The side chains of R/L566 and @VARIANT$ are shown as sticks, and the other residues are shown as lines. (D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.R566L, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (p.R297C, @VARIANT$).",7279190,FLNB;37480,TTC26;11786,A/T2282;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/@GENE$ (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,1
GFP-@GENE$ R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2).,5953556,CYP1B1;68035,TEK;397,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"However, none of these signs were evident from metabolic work of the patient with @GENE$ L718F, thus ruling out pathogenic significance of this variant. Pathogenic effects of @GENE$ @VARIANT$ and NDUFS8 @VARIANT$ variants remain unknown.",6072915,PHKA1;1981,GBE1;129,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"  To gain further insight into the role of EphA2 on pendrin regulation, @GENE$ A372V, L445W, Q446R or @VARIANT$ was co-overexpressed with EphA2. The cells were transfected with cDNAs of encoding myc-pendrin diease forms with that of @GENE$, and the non-permeable cells were stained with an anti-myc antibody. While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, Q446R, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), @VARIANT$ (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,pendrin;20132,EphA2;20929,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,Ser166 to Asn;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both @GENE$ recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"We identified four genetic variants (@GENE$-@VARIANT$, @GENE$-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,REEP4;11888,HS1BP3;10980,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PRICKLE4;22752,FZD1;20750,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ T168fsX191 mutation, but not the TNFRSF13B/TACI C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 @VARIANT$ gene. Exons coding E2A functional domains, activation domain 1 and 2 (@GENE$, AD2) and helix-loop-helix (HLH) domains are shown.",5671988,TCF3;2408,AD1;56379,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Similarly, SH170-377 carrying the @VARIANT$ mutation in @GENE$ also contained a previously reported homozygous @VARIANT$*36 mutant allele in Myosin XVA (@GENE$) (NM_016239) (Table 1).",4998745,GJB2;2975,MYO15A;56504,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.Glu396Argfs;tmVar:p|FS|E|396|R|;HGVS:p.E396RfsX;VariantGroup:15;CorrespondingGene:51168;RS#:772536599;CA#:8423043,1
"(c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of @GENE$ @VARIANT$ mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), @GENE$ @VARIANT$ showed a decreasing trend in molecular weight and increasing instability.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes.     ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The @VARIANT$ (c.1045G>A) mutation in exon 9 of EDA and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of WNT10A were detected.",3842385,EDA;1896,WNT10A;22525,p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"                                 CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and @GENE$ p.R1865H by WES and predisposing genes analyses. More cellular and animal research is needed to further investigate whether the coexisting interaction of KCNH2 @VARIANT$ and SCN5A @VARIANT$ increases the risk of the early-onset LQTS and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, @VARIANT$, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.1556G>A;tmVar:c|SUB|G|1556|A;HGVS:c.1556G>A;VariantGroup:9;CorrespondingGene:4647;RS#:111033206;CA#:278629,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"                            The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the @GENE$/FGFR1 signalling pathway. FGFR1 signalling is essential for the migration, secretion, or survival of hypothalamic GnRH neurons and is widely expressed in the nervous and skeletal systems. The FGFR1 gene is inherited through an autosomal dominant mode. Loss of function can lead to both nIHH and KS, and more than 200 variants of the @GENE$ gene have been found in patients with IHH. The FGFR1 gene had the highest variant frequency, approximately 44% in our study, which was higher than that (10%) in the Caucasian population. Its variant can cause cleft lip and palate, short stature, and bone dysplasia. Among the 11 FGFR1 variants reported in our study, @VARIANT$ (p. Arg254Gln), c.232C > T (p. Arg78Cys), and c.2008G > A (@VARIANT$) were found to be pathogenic variants.",8796337,FGF;8822;8822,FGFR1;69065,c.761G > A;tmVar:c|SUB|G|761|A;HGVS:c.761G>A;VariantGroup:6;CorrespondingGene:268;RS#:753231264;CA#:9062967,p. Glu670Lys;tmVar:p|SUB|E|670|K;HGVS:p.E670K;VariantGroup:1;CorrespondingGene:2260;RS#:397515446;CA#:143804,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"@GENE$ forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The c.1592G>A (p.Cys531Tyr) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant @VARIANT$ (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in @GENE$/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant c.2075A>G (@VARIANT$) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions.",6161649,SCUBE2;36383,BMP;55955,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,p.Asn692Ser;tmVar:p|SUB|N|692|S;HGVS:p.N692S;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,0
"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,GJB6;4936,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,UBQLN2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"The c.1592G>A (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking @GENE$ activity in @GENE$/TGF-beta signalling (figure 3).",6161649,SMAD1;21196,BMP;55955,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"However, it was hard to determine whether the coexisting interactions of @GENE$ p.307_308del and SCN5A @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while @GENE$ mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 @VARIANT$ and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Using SIFT and PolyPhen, the @VARIANT$ variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in EHMT1 and c.353A > G (@VARIANT$) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,SLC9A6;55971,MFSD8;115814,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, p. A85P, p.L86F, @VARIANT$, p.R127L, @VARIANT$, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,p.G149D;tmVar:p|SUB|G|149|D;HGVS:p.G149D;VariantGroup:15;CorrespondingGene:1805;RS#:777651623,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,PDGFRB;1960,SLC20A2;68531,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB2;2975,gap junction protein beta 3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in EHMT1 and @VARIANT$ (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (@GENE$ @VARIANT$ at a rate of 4.95 x 10-5, MFSD8 c. 353A > G at a rate of 8.24 x 10-6).",7463850,MFSD8;115814,EHMT1;11698,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ p.R769W, @GENE$ @VARIANT$, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"    A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,alsin;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin F355L mutations on @GENE$ interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,EphA2;20929,ephrin-B2;3019,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female @GENE$-@VARIANT$ mutation carriers, which led to the incomplete penetrance.",5426766,SCN5A;22738,CACNA1C;55484,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,1
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), @VARIANT$, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"However, it was hard to determine whether the coexisting interactions of @GENE$ p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and @GENE$ p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 @VARIANT$ and SCN5A @VARIANT$ by WES and predisposing genes analyses.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (@GENE$) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,OPTN;11085,TANK-binding kinase 1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates                TOR2A missense variant A TOR2A nonsynonymous SNV (@VARIANT$ [NM_130459.3], p.Arg190Cys [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,REEP4;11888,BSP+;3644,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Her mother with c.1339 + 3A>T in COL4A5 and her father with a missense mutation c.4421C > T in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes.",6565573,COL4A4;20071,COL4A3;68033,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"@GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,DFNB1;2975,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ @VARIANT$), 2F07 (@GENE$ @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A).",5887939,PRICKLE4;22752,CELSR1;7665,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB6;4936,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:@VARIANT$; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to @GENE$ in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (CSF1R), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (FUS).       CNV analysis of the 21 neurodegenerative disease genes using Ingenuity Variant Analysis software further identified one patient with a partial deletion of OPTN (NM_001008211.1:@VARIANT$; p.Gly538Glufs27).",4470809,TBK1;22742,OPTN;11085,c.2086G>A;tmVar:c|SUB|G|2086|A;HGVS:c.2086G>A;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,c.1243-740_1612+1292delins25;tmVar:c|INDEL|1243-740_1612+1292|25;HGVS:c.1243-740_1612+1292delins25;VariantGroup:37;CorrespondingGene:10133,0
This indicates that neither p.R143W in @GENE$ nor @VARIANT$ in @GENE$ contributed to SNHL in SH60-136 and that @VARIANT$ in GJB2 was an incidentally detected variant in this subject.,4998745,GJB2;2975,WFS1;4380,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,0
"The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of @GENE$ were extracted, which revealed one common variant (c.-9 + 342A > G) in intron 1 with a MAF of 0.3 according to GnomAD.",8446458,SEMA7A;2678,PROKR2;16368,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
"We propose that @VARIANT$ of @GENE$ lacks activity to bind DNA reducing the transactivation of AMH critically.  By contrast, variants p.Pro226Leu and p@VARIANT$ found in cases 2 and 3 did not affect @GENE$ promoter activity.",5893726,GATA4;1551,CYP17;73875,cysteine to arginine change in position 238;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT6;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 @VARIANT$ and @GENE$ p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (@VARIANT$), @GENE$ (rs143445685), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,RYR1;68069,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB6;4936,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"However, none of these signs were evident from metabolic work of the patient with @GENE$ @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of @GENE$ D413N and NDUFS8 @VARIANT$ variants remain unknown.",6072915,PHKA1;1981,GBE1;129,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0
"(a) Digenic inheritance of @GENE$ (c.310T>C, C104R TACI) and TCF3 (T168fx191) mutations in a three-generation New Zealand family. Whole-exome sequencing was performed on II.2, III.1 and III.2 (indicated by *). The proband (II.2) is indicated by an arrow. Circles, female; squares, male; gray, TNFRSF13B/TACI @VARIANT$ mutation; blue TCF3 T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations are shown.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
II: 1 carried the digenic heterozygous mutations of @GENE$ @VARIANT$ and @GENE$ @VARIANT$. I: 1 and II: 2 were heterozygous for SCN5A p.R1865H.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1
"Sequestosome-1 (@GENE$, chr.5) is a scaffolding protein involved in multiple cellular processes, including apoptosis, cell survival, and autophagy. Its numerous domains allow SQSTM1 to serve as a frame for multiprotein complexes and regulator of ubiquitinated protein turnover. SQSTM1 mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.2857A > G @VARIANT$) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and @VARIANT$ (c.1051 G > A p.G351R), have already been described in the literature.",3975370,NOD2;11156,IL10RA;1196,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,rs2229113;tmVar:rs2229113;VariantGroup:0;CorrespondingGene:3587;RS#:2229113,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, @VARIANT$, p.Tyr27His), @GENE$ (NM_018328.4, c.2000T>G, @VARIANT$), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"A, The pedigree shows the coinheritance of the monoallelic variants which encode @GENE$ @VARIANT$ and @GENE$ @VARIANT$ in a family affected by colorectal cancer.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, @VARIANT$, p. A85P, p.L86F, @VARIANT$, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,FOXC1;20373,PITX2;55454,p.S82T;tmVar:p|SUB|S|82|T;HGVS:p.S82T;VariantGroup:111;CorrespondingGene:6012,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,SPTBN4;11879,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with BSP+ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates                @GENE$ missense variant A TOR2A nonsynonymous SNV (@VARIANT$ [NM_130459.3], p.Arg190Cys [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,REEP4;11888,TOR2A;25260,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, @VARIANT$, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The @VARIANT$ (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A.",3125325,MYO7A;219,USH1C;77476,c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"  In patient AVM427, the de novo heterozygous missense variant c.3442G>T (@VARIANT$) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating BMP signalling. In addition to Smad1-mediated BMP signalling, @GENE$ also interacts with Smad4 to mediate Smad2-Smad4 complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, c.1891G>T (p.Glu631Ter), in EGFR (table 1). Oncogenic EGFR stimulates angiogenesis via the VEGF pathway. As a truncated germline EGFR variant has not been reported in humans, @VARIANT$ (p.Glu631Ter) in patient AVM312 was classified as likely pathogenic and EGFR as a candidate gene due to the vital role of @GENE$ in EGF and VEGF signalling.",6161649,ZFYVE16;8826,EGFR;74545,p.Asp1148Tyr;tmVar:p|SUB|D|1148|Y;HGVS:p.D1148Y;VariantGroup:3;CorrespondingGene:9765,c.1891G>T;tmVar:c|SUB|G|1891|T;HGVS:c.1891G>T;VariantGroup:8;RS#:909905659,0
"The mother did not carry this luteinizing hormone/choriogonadotropin receptor (@GENE$) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, SRY, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described @VARIANT$ mutant. By contrast, GATA4 variants @VARIANT$ and Pro226Leu activated the CYP17 promoter similar to wt. Transcriptional activity of GATA4 variants on the @GENE$ promoter.",5893726,LHCGR;37276,CYP17A1;73875,Gly221Arg;tmVar:p|SUB|G|221|R;HGVS:p.G221R;VariantGroup:4;CorrespondingGene:2626;RS#:398122402(Expired),Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"@VARIANT$ lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this G-protein coupled receptor, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, @GENE$, KAL1, GNRHR, GNRH1, or @GENE$. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;@VARIANT$ from NP_056352).",3888818,TAC3;7560,KISS1R;11411,Trp275;tmVar:p|Allele|W|275;VariantGroup:1;CorrespondingGene:6870;RS#:144292455,p.Thr478Ala;tmVar:p|SUB|T|478|A;HGVS:p.T478A;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The following genes showed variants in two patients: CYP1A1 in patients 1 and 6; @GENE$ in patients 1 (2 variants) and 7; IRX5 in patients 5 and 6; MAML1 in patients 4 and 6; MAML2 in patients 5 and 8; NOTCH2 in patients 5 and 7; RECQL4 in patients 2 and 3 and WDR11 in patients 6 and 7 ( Table 2 ). In addition, 2 genes presented variants in 3 patients: MAML3 (patients 6, 7 and 8) and NOTCH1 (patients 1, 4 and 8). Furthermore, @GENE$ presented 2 variants in patient 1. Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,EVC;10949,RIPK4;10772,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, @VARIANT$ (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the @VARIANT$ substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"All exons including the 5' and 3' untranslated regions of the @GENE$, @GENE$, SCN5A, KCNE1, and KCNE2 genes were amplified by polymerase chain reaction (PCR). The PCR products were screened for mutations by direct sequencing (Applied Biosystems Big-Dye Terminator v1.1 cycle sequencing kit; Life Technologies, Grand Island, NY, USA) with an Applied Biosystems Prism 3100 DNA Analyzer (Life Technologies, Grand Island, NY, USA) using previously reported protocols. In silico predictions of pathogenicity were made using the Alamut  Visual software (Interactive Biosoftware, Rouen, France), and population allele frequencies were determined using the ExAC Browser (Beta) database.      4.3. Mutagenesis Sequence variants KCNH2-c.G323A (@VARIANT$) and KCNQ1-c.G1748A (@VARIANT$) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously.",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG p.P136L, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,DCTN1;3011,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"2.3. Functional Consequences of the @GENE$-p.R583H and KCNH2-p.C108Y Variants To investigate the functional consequences of KCNQ1-@VARIANT$ and @GENE$-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Functional impact of the rare variants The two missense @GENE$ variants (@VARIANT$ and (p.(C498R)) and one of the @GENE$ amino acid substitutions (@VARIANT$) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (@VARIANT$), @GENE$ (c.607C>T) and @GENE$ (@VARIANT$) genes.",7877624,SNAI2;31127,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"The results showed that, in addition to the @GENE$ gene variant [p.(@VARIANT$)], a second variant in @VARIANT$ in the @GENE$ gene was involved in the second highest number of pathogenic digenic combinations (15%), with 18 other variants in 13 genes.",8446458,PROKR2;16368,CCDC141;52149,Pro290Ser;tmVar:p|SUB|P|290|S;HGVS:p.P290S;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,1
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,ENG;92,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,0
"(A) In addition to c.235delC in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB3;7338,GJB2;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,VAPB;36163,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, @VARIANT$ in @GENE$, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (EHMT1 @VARIANT$ at a rate of 4.95 x 10-5, MFSD8 c. 353A > G at a rate of 8.24 x 10-6).",7463850,EHMT1;11698,MFSD8;115814,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A).",5887939,CELSR1;7665,FAT4;14377,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,0
"Both the aborted foetuses carried the compound heterozygous pathogenic variants, namely @GENE$: c.1386-2A > G and PKD1: c.7583A > G (p.Y2528C) from each parent, and these variants were inferred to have contributed to the foetal PKD. 33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the PKD1: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: @VARIANT$ (p.R559W) and PKHD1: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.1675C > T;tmVar:c|SUB|C|1675|T;HGVS:c.1675C>T;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488,0
"The other two LRP6 variants, c.2450C>G (p.Ser817Cys) and c.4333A>G (@VARIANT$), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the WNT10A mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance. Segregation analysis of the parent-child trio revealed that the father, who was hypodontic, carried all three @GENE$ variants but not the @GENE$ mutation, which was found in the mother.",8621929,LRP6;1747,WNT10A;22525,p.Met1445Val;tmVar:p|SUB|M|1445|V;HGVS:p.M1445V;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"        Cardiac Phenotype: A @GENE$/@GENE$ Genetic Interaction The cardiac phenotype in the indexed-family is divided into two: a mild VSD not requiring any intervention and a severe TOF-like phenotype that required major intervention (Figure 1). We sought that differential variants inherited from the father would contribute to this differential expressivity of the ARS phenotype within the three affected children in this family: two with a cardiac phenotype and the third with only glaucoma. Interestingly, we unravel two novel missense mutations in OBSCN (@VARIANT$) and NFATC1 (@VARIANT$) that are predicted to be damaging (Table 4).",5611365,FOXC1;20373,NFATC1;32336,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"Moller et al. reported an index case with digenic variants in MYH7 (L1038P) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in @GENE$ (@VARIANT$) and TNNT2 (Asn83His), both sarcomeric genes.",6359299,MYBPC3;215,MYH7;68044,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (@VARIANT$), RYR1 (rs143445685), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,COL6A3;37917,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"This included the variants in @GENE$ (chr6, NM_000426.3:@VARIANT$ (p.Thr127Ala); MAF 1.76 x 10-5) and @GENE$ (chr10, NM_0002211:@VARIANT$ (p.Glu562del); MAF 3.871 x 10-5), which affected amino acid residues that were found to be highly conserved across species (Fig. 1).",8474709,LAMA2;37306,LOXL4;12977,c.380A > G;tmVar:c|SUB|A|380|G;HGVS:c.380A>G;VariantGroup:0;CorrespondingGene:3908,c.1684_1686del;tmVar:c|DEL|1684_1686|;HGVS:c.1684_1686del;VariantGroup:5;CorrespondingGene:84171,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with VAPB p.M170I and @GENE$ p.R408C with SETX @VARIANT$ and SETX p.T14I).",4293318,ANG;74385,TAF15;131088,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (@VARIANT$) and @GENE$: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.R566L, p.@VARIANT$) vector plasmids and myc-tagged WT or mutant TTC26 (p.R297C, @VARIANT$). Then, communoprecipitation assays were conducted. Western blot images are representative of n=3 experiments. AIS, adolescent idiopathic scoliosis; WT, wild type. To investigate the protein-protein interactions, we focused on AIS trios with multiple variants. We found that patients in two AIS trios (trios 22 and 27) carried variants in both the @GENE$ and @GENE$ genes (figure 1).",7279190,FLNB;37480,TTC26;11786,A2282T;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,0
"One possible explanation for this could be that @VARIANT$ (p.R213C) was possibly a hypomorphic variant. 47  The TMEM107 gene is expressed in a subset of embryonic tissues 48  and is involved in cilia formation. This gene was designated as the causative gene for MKS13. 49  The proband foetus with typical @GENE$ phenotypes in Family 25 carried two novel TMEM107 variants: @VARIANT$ (p.E44Rfs*98) and c.64_66delGTC (p.V22del), both of which were predicted with large fragment truncation and were expected to cause a functional defect.   In the final report, two cases of adult-onset (families 19 and 20) and one case of foetal-onset (Family 26) presented negative results. The causes might include mosaicism, variants outside the exons, inversion and epigenetic change, among others. Recent studies have indicated that @GENE$ mosaicism occurring in the early-stage embryos might respond to a few of the unsolved cases 50  and could explain the intra-familial phenotype variability.",8256360,MKS13;12052,PKD1;250,c.637C > T;tmVar:c|SUB|C|637|T;HGVS:c.637C>T;VariantGroup:3;CorrespondingGene:5314;RS#:866575098;CA#:138924774,c.129delC;tmVar:c|DEL|129|C;HGVS:c.129delC;VariantGroup:7;CorrespondingGene:84314;RS#:745751675,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The DUSP6 gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,SEMA7A;2678,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Notably, the patients carrying the @VARIANT$ and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROK2;9268,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: @VARIANT$ (p.434A>T), @GENE$: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, @VARIANT$, p.L86F, p.F112S, @VARIANT$, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,FOXC1;20373,PITX2;55454,p. A85P;tmVar:p|SUB|A|85|P;HGVS:p.A85P;VariantGroup:78;CorrespondingGene:6012,p.R127L;tmVar:p|SUB|R|127|L;HGVS:p.R127L;VariantGroup:19;CorrespondingGene:2296;RS#:1085307884,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,DFNB1;2975,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"II: 1 carried the digenic heterozygous mutations of KCNH2 @VARIANT$ and SCN5A p.R1865H. I: 1 and II: 2 were heterozygous for @GENE$ @VARIANT$. Except II: 1, other family members did not carry @GENE$ mutation.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,VAPB;36163,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and @GENE$. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).",7279190,FLNB;37480,TTC26;11786,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, @VARIANT$ (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C TTC26 proteins pulled down the Flag-tagged mutant p.A2282T and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ FLNB and p.Y437F @GENE$ (figure 3D).  @GENE$ and OFD1 variants in individuals with AIS. (A) Pedigree of AIS twins.",7279190,OFD1;2677,FLNB;37480,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,0
"Using a Bonferonni-corrected significance level of 8.2x10-4, 3 variants were significantly more common in our ALS discovery cohort (rs3739927 and @VARIANT$ in SETX, and @VARIANT$ in EWSR1). To follow up, we genotyped these 3 SNPs and 28 additional candidate variants in a validation cohort of 552 sporadic ALS cases and 464 controls from Coriell reference panels. However, none of the 31 tested variants showed a significant association with ALS in either direction (Supplementary Table 2).    We also asked whether the burden of rare coding variants in any of the tested ALS genes was higher in sporadic subjects compared to controls using SKAT (Table 5). After correcting for multiple tests (alpha=3.57x10-3), @GENE$ was the only gene that showed a significant association (p=1.59x10-5) while @GENE$ and VAPB approached statistical significance (p=5.57x10-3 and p=5.99x10-3 respectively).",4293318,SOD1;392,TARDBP;7221,rs882709;tmVar:rs882709;VariantGroup:27;CorrespondingGene:23064;RS#:882709,rs41311143;tmVar:rs41311143;VariantGroup:21;CorrespondingGene:2130;RS#:41311143,0
"For example, two variants in proband P15, @VARIANT$ in PROKR2 and @VARIANT$ in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while @GENE$ p. Gln1626His variant was inherited from unaffected mother.",8152424,DCAF17;65979,DMXL2;41022,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,0
"The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A3;2223,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"@GENE$ and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and @VARIANT$ (p.Ser334Thr) were identified in PTPN13 (table 2).",6161649,DSCAML1;79549,DSCAM;74393,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and @GENE$ @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,1
"The @VARIANT$ and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both PKD1 and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(Cys331Thr) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in PKD2, p.(@VARIANT$).",7224062,PKD2;20104,PKD1;250,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, @VARIANT$ or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (c.965delA), SNAI2 (@VARIANT$) and C2orf74 (@VARIANT$) genes. Variant in @GENE$ is not segregating with the disease phenotype therefore it was excluded as an underlying cause of WS2 in the family.",7877624,MITF;4892,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, @VARIANT$, p.S82T, p. A85P, p.L86F, p.F112S, @VARIANT$, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.P79T;tmVar:p|SUB|P|79|T;HGVS:p.P79T;VariantGroup:108;CorrespondingGene:6012,p.R127L;tmVar:p|SUB|R|127|L;HGVS:p.R127L;VariantGroup:19;CorrespondingGene:2296;RS#:1085307884,0
"Three variants in three genes were rare, including the @GENE$ gene mutation [p.(Lys205del)], a novel heterozygous missense variant [@VARIANT$; p.(@VARIANT$)] in the @GENE$ gene (NM_001146029), as well as a splice site variation in the PLXNA1 gene (NM_032242; MAF = 0.03 in GnomAD).",8446458,PROKR2;16368,SEMA7A;2678,c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
Mutations of KCNH2 and @GENE$ genes are closely related to LQTS. The mutations of @GENE$ @VARIANT$ and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.,8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 @VARIANT$ and SCRIB c.3979G>A). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 @VARIANT$), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PTK7;43672,FZD6;2617,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0
"The @VARIANT$ variant alters an amino acid that is highly conserved among vertebrates (Figure 5). Another candidate variant in MYH13 (rs7807826) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of MYH13 is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: @VARIANT$, p.Arg687*; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs. ATP2A3 is highly expressed in cerebellar Purkinje cells (Allen Brain Atlas) and is a member of the P-type ATPase superfamily that includes the gene (ATP1A3) causally associated with rapid-onset dystonia-Parkinsonism (@GENE$).",6081235,NOS2;55473,DYT12;113729,Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,c.2059C>T;tmVar:c|SUB|C|2059|T;HGVS:c.2059C>T;VariantGroup:11;RS#:200336122,0
"Sequence alterations were detected in the @GENE$ (rs144651558), RYR1 (@VARIANT$), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,COL6A3;37917,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB @VARIANT$, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (@VARIANT$), SNAI2 (c.607C>T) and @GENE$ (@VARIANT$) genes.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,1
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"This individual was also heterozygous for the common MTHFR c.677C>T variant, and also carries a rare glycine decarboxylase (@GENE$) @VARIANT$ missense variant, possibly indicating a compromised FOCM in this patient. Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (c.7549G>A; @VARIANT$) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (@GENE$) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3).",5887939,GLDC;141,CELSR1;7665,c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332,p.Val2517Met;tmVar:p|SUB|V|2517|M;HGVS:p.V2517M;VariantGroup:14;CorrespondingGene:9620;RS#:1261513383,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 @VARIANT$ and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PRICKLE4;22752,CELSR2;1078,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; @VARIANT$, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,g.124339A>G;tmVar:g|SUB|A|124339|G;HGVS:g.124339A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6).",6610752,LQT2;201,KCNE2;71688,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Similarly, the @GENE$-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and @GENE$ @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,CCDC88C;18903,FGFR1;69065,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Mutations in @GENE$ and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; @VARIANT$) @VARIANT$; p.N409S and @GENE$ (MIM 600509; NM_000352.4; rs151344623) c.3989-9G>A mutations.,5505202,GBA;68040,ABCC8;68048,rs7673715;tmVar:rs7673715;VariantGroup:2;RS#:7673715,c.1226A>G;tmVar:c|SUB|A|1226|G;HGVS:c.1226A>G;VariantGroup:7;CorrespondingGene:2629;RS#:76763715;CA#:116767,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, @GENE$ p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0
"Five subjects (R279, R410, R465, R469 and R470) carried pathogenic and deleterious variants in genes known to affect glycogen metabolism (GBE1, PYGM), FAO (ACADVL and CPT2), fatty acid and amino acid catabolism (PCCB), oxidative phosphorylation (@GENE$, NDUFA6, NDUFA10 and NUBPL), mitochondrial matrix enzymes (OAT and TIMM50). Two subjects (R302 and R462) had variants in genes involved in Ca 2+ regulation (RYR1 and CACNA1S), glycogen metabolism (GBE1 and PHKA1) and oxidative phosphorylation (NDUFS8). Mutations in PHKA1 cause Glycogen Storage Disease type IX, X-linked phosphorylase kinase (PHK) enzyme deficiency, characterized by high muscle glycogen content and severe reduction of muscle @GENE$ activity. However, none of these signs were evident from metabolic work of the patient with PHKA1 L718F, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 @VARIANT$ and NDUFS8 @VARIANT$ variants remain unknown.",6072915,ELAC2;6403,PHK;246,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD6;2617,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, @VARIANT$), @GENE$ p.A961T (NM_000426, @VARIANT$), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,LAMA2;37306,KCNH2;201,c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0
"In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in @GENE$ (OMIM 612981; rs146322628, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in UBR4 (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and @GENE$ (OMIM 612496; @VARIANT$, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,IMP4;68891,ARHGEF19;17710,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,rs144638812;tmVar:rs144638812;VariantGroup:0;CorrespondingGene:128272;RS#:144638812,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB6;4936,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"Quantification of cells with dilated endoplasmic reticulum (ER) and COPII vesicles associated with Golgi by transmission electron microscopy Genotype of cell line Cells with dilated ER (%) Cells with Golgi-associated vesicles (%) Wt (N = 414) 2 (0.5) 309 (75) SEC23A@VARIANT$/+ (N = 83) 83 (100***) 9 (11***) SEC23Ac.1200G>C/+ MAN1B1@VARIANT$/+ (N = 190) 190 (100***) 3 (1.6***) SEC23Ac.1200G>C/c.1200G>C; MAN1B1c.1000C>T/c.1000C>T (N = 328) 328 (100***) 2 (0.6***)  Increased Intracellular and Secreted Pro-COL1A1 in Fibroblasts with Homozygous Mutations in Both @GENE$ and @GENE$ in the Presence of l-Ascorbic Acid SEC23A is required for normal transport of pro-COL1A1, a major extracellular matrix component of bone.",4853519,SEC23A;4642,MAN1B1;5230,c.1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"                            The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the @GENE$/@GENE$ signalling pathway. FGFR1 signalling is essential for the migration, secretion, or survival of hypothalamic GnRH neurons and is widely expressed in the nervous and skeletal systems. The FGFR1 gene is inherited through an autosomal dominant mode. Loss of function can lead to both nIHH and KS, and more than 200 variants of the FGFR1 gene have been found in patients with IHH. The FGFR1 gene had the highest variant frequency, approximately 44% in our study, which was higher than that (10%) in the Caucasian population. Its variant can cause cleft lip and palate, short stature, and bone dysplasia. Among the 11 FGFR1 variants reported in our study, @VARIANT$ (p. Arg254Gln), @VARIANT$ (p. Arg78Cys), and c.2008G > A (p. Glu670Lys) were found to be pathogenic variants.",8796337,FGF;8822;8822,FGFR1;69065,c.761G > A;tmVar:c|SUB|G|761|A;HGVS:c.761G>A;VariantGroup:6;CorrespondingGene:268;RS#:753231264;CA#:9062967,c.232C > T;tmVar:c|SUB|C|232|T;HGVS:c.232C>T;VariantGroup:10;CorrespondingGene:2260,0
"The proband's son (III.1) has inherited the @GENE$ @VARIANT$ mutation, but not the TNFRSF13B/@GENE$ @VARIANT$ mutation.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"                    By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in @GENE$ allele harbored a single heterozygous p.A194T mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). This 2-year-old female showed severe autosomal recessive SNHL with a mean hearing threshold of 87.5 dB HL.   Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the p.T123N variant of GJB2. The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of USH2A (NM_007123), R5143C, C4870F, and @VARIANT$ with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and @GENE$ (ANK1) identified in SH 94-208).",4998745,GJB2;2975,Ankyrin 1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,G805A;tmVar:c|SUB|G|805|A;HGVS:c.805G>A;VariantGroup:14;CorrespondingGene:7399;RS#:587783023;CA#:270788,0
Merged images showing pro-COL1A1 colocalization with @GENE$ in wild-type (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ MAN1B1R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ @GENE$R334C/@VARIANT$ double-homozygous (L) fibroblasts.,4853519,TGN38;136490,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Capillary zone electrophoresis was used to obtain the chromatogram of transferrin isoforms in (A) @GENE$ M400I/+ heterozygous; (B) SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; (C,D) SEC23AM400I/@VARIANT$ @GENE$R334C/@VARIANT$ double homozygous mutant serum.",4853519,SEC23A;4642,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Importantly, he had no coexistent mutations in @GENE$, FGF8, FGFR1, PROK2, PROKR2, TAC3, @GENE$, KAL1, GNRHR, GNRH1, or KISS1R. The second patient (KS male C7) had a heterozygous c.757G>A (p.Ala253Thr) mutation (Figure 1; Table 1) affecting a completely conserved Ala253 residue (Figures S1-4). Using multiple sequence alignment (ESPRESSO), a protein model for the N-terminus was constructed. Both SSPIDER and INTERPROSURF analysis (Figure S4) suggest functional importance for Ala253; and SIFT predicts a deleterious effect for p.Ala253Thr. Although @VARIANT$ did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously.",3888818,CHD7;19067,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel @GENE$ missense variant @VARIANT$).",5887939,FZD6;2617,FAT4;14377,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"(A) Segregation of the @GENE$-p.R583H, @GENE$-p.C108Y, KCNH2-@VARIANT$, and KCNE1-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNQ1;85014,KCNH2;201,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,alsin;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
" Finally, a subject with the heterozygous p.R143W mutation in @GENE$ (SH60-136) carried a @VARIANT$ variant in @GENE$ (WFS1) (NM_001145853) according to TES. However, neither @VARIANT$ in GJB2 nor p.D771N in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).",4998745,GJB2;2975,Wolfram syndrome 1;4380,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,0
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Allele frequency for @VARIANT$ within the population was calculated from exome sequencing of 2000 individuals and was found to be 0.1% (unpublished data from the Saudi Human Genome Project; www.saudigenomeprogram.org). Furthermore, 500 ethnically matched normal controls were genotyped for this change by re-sequencing of @GENE$. Three of these individuals were heterozygous, but none was homozygous for rs138355706. Sequencing of the S100A3 intronic and 5'-flanking sequences was performed in the affected patients and no other variants were identified (data not shown). The novel truncated variant in @GENE$ was not found in our ""in-house"" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The c.229C>T (p.R77C) variant in S100A3 and @VARIANT$ (p.I80Gfs*13) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.",6637284,S100A3;2223,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
" @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2).",6161649,ENG;92,BMP;55955,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, @VARIANT$ in @GENE$, and @VARIANT$ and c.10712C>T in USH2A.",3125325,MYO7A;219,USH1C;77476,c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,CCNF;1335,alsin;23264,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"No mutations in SLC5A5, @GENE$, or @GENE$ gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) DUOX2:c.3329G>A (@VARIANT$) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,TPO;461,IYD;12352,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Given the reported normal function of pendrin @VARIANT$ and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both @GENE$ recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"The proband's son (III.1) carrying only the heterozygous TCF3 @VARIANT$ mutation is also able to produce some IgG in vitro via activation of both pathways, but at much lower levels than his wild-type sister (III.2). His cells produced higher levels of IgG and IgM than his mother (II.2, who bears both the TNFRSF13B/@GENE$ @VARIANT$ and @GENE$ T168fsX191 mutations).",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
@GENE$ @VARIANT$ may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. @GENE$ @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"(A) In addition to @VARIANT$ in GJB2, the de novo variant of @GENE$, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the @GENE$ locus. (C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates.",4998745,MITF;4892,DFNB1;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,VAPB;36163,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"By contrast, the expression of human @GENE$ and @GENE$, either alone or in combination, did not restore the viability of the mutant (Fig 3C), suggesting that the human orthologs have evolved in structure and function in comparison to Gcn5. As the mutated amino acid in KAT2B, F307, is conserved in Drosophila Gcn5 (corresponding to Gcn5 F304), we re-expressed Gcn5 F304S in the Gcn5E333st hemizygous background (Gcn5 F304S). As a negative control, we re-expressed a predicted potentially damaging KAT2B variant (@VARIANT$ corresponding to Gcn5 @VARIANT$) found in a homozygous state in a healthy individual from our in-house database.",5973622,KAT2A;41343,KAT2B;20834,S502F;tmVar:p|SUB|S|502|F;HGVS:p.S502F;VariantGroup:3;CorrespondingGene:8850;RS#:141445570;CA#:2284662,S478F;tmVar:p|SUB|S|478|F;HGVS:p.S478F;VariantGroup:13;CorrespondingGene:2648,0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with @GENE$ is supported by data showing that @GENE$ and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx31;7338,Cx26;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS7;12395,BBS6;10318,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated @GENE$ mutation (c.1403 C > T; @VARIANT$) and a novel, potentially pathogenic missense @GENE$ variant (@VARIANT$; p.P340S) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,PTPN11;2122,SOS1;4117,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,c.1018 C > T;tmVar:c|SUB|C|1018|T;HGVS:c.1018C>T;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,1
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel FAT4 missense variant @VARIANT$).",5887939,CELSR2;1078,FZD6;2617,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"Although the majority of @GENE$ mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging.       In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel @VARIANT$ deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The NEK1 R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    @GENE$ variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and @VARIANT$).",6707335,FUS;2521,CCNF;1335,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,0
"Sequence alterations were detected in the @GENE$ (@VARIANT$), RYR1 (rs143445685), @GENE$ (@VARIANT$), and DES (rs144901249) genes.",6180278,COL6A3;37917,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"In this family, the TNFRSF13B/@GENE$ @VARIANT$ mutation appears to demonstrate a gene dosage effect on serum IgG levels. The brother who is homozygous (II.4) for the TNFRSF13B/TACI C104R mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"18  @GENE$ is implicated in inflammatory bowel disease and various cancer types, although primarily due to loss-of-function somatic mutations. 18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by OGG1. 20  The identified CUX1 (NM_001202543: c.1438A > G, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  @GENE$, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: @VARIANT$, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,CUX1;22551,TRIP6;37757,c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"@GENE$ @VARIANT$ and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for @GENE$ @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel @GENE$ missense variant (@VARIANT$) with a rare @GENE$ missense variant (c.1892C>T).",5887939,PTK7;43672,CELSR2;1078,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,0
"While tagged versions of EphA2 @VARIANT$ and EphA2 T511M were effectively precipitated with Fc-fusion ephrin-A1 compared to @GENE$ WT, Fc-fusion ephrin-B2 failed to pull down EphA2 G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 G355R and EphA2 T511M with pendrin induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause @GENE$ cytoplasmic localization. A subset of these mutations, such as H723R, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum. Low temperature incubation and salicylate treatment of cultured cells, which are thought to help with protein-folding processes, rescues the membrane localization of @VARIANT$. On the other hand, mis-localization of pendrin A372V from the plasma membrane is not restored by these treatments, suggesting these mutations may affect pendrin trafficking from the Golgi to the plasma membrane but not protein-folding.",7067772,EphA2;20929,pendrin;20132,G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0
"We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous @GENE$ mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We did not find a mutation in FGFR1 in any of the individuals carrying a mutation in PROKR2 or @GENE$, either. However, one of the patients heterozygous for the @VARIANT$ mutation in PROKR2 (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in @GENE$ exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,PROK2;9268,KAL1;55445,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0
"Interestingly, we unravel two novel missense mutations in OBSCN (@VARIANT$) and NFATC1 (@VARIANT$) that are predicted to be damaging (Table 4). Both variants are neither present in the Lebanese controls nor in the genome and exome databases. Given that OBCSN mutations have not been linked to CHD, but could be potentially causing cardiomyopathies, we hypothesize that the @GENE$ missense variant along the @GENE$ variant is responsible for the cardiac phenotype.",5611365,NFATC1;32336,FOXC1;20373,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,0
"On the other hand, mutant GFP-@GENE$ @VARIANT$ and R368H showed perturbed interaction with HA-TEK. The residues E103, I148, and @VARIANT$ lie in the N-terminal extracellular domain of @GENE$ (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214;tmVar:p|Allele|Q|214;VariantGroup:10;CorrespondingGene:7010,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"(d) Electropherograms of unaffected family member (II-1) and proband (II-2) show @GENE$ variant. (e) Multiple sequence alignment shows evolutionary conservation of @VARIANT$ among vertebrates               A @GENE$ frameshift variant (@VARIANT$ [NM_004297.3], p.Thr330ArgfsTer67 [NP_004288.1]) was also identified in the same pedigree (Family 10043) and is present at low frequency in gnomAD (1.23E-05) (Figure 6; Tables 1, 5, and 8 and S2; Data S1).",6081235,HS1BP3;10980,GNA14;68386,Gly32;tmVar:p|Allele|G|32;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"To examine whether @GENE$ is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Moreover, this @GENE$ variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/MITF and GJB2/@GENE$ (group II). (A) In addition to c.235delC in GJB2, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3.",4998745,MITF;4892,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
Other family members who have inherited @GENE$ @VARIANT$ and @GENE$/TACI @VARIANT$ mutations are shown.,5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The proband and her sister, both with severe skin findings with extensive mineralization, were compound heterozygotes for missense mutations in the @GENE$ gene, which were shown to result in reduced gamma-glutamyl carboxylase activity and in under-carboxylation of matrix gla protein. The proband's mother and aunt, also manifesting with PXE-like skin changes, were heterozygous carriers of a missense mutation (@VARIANT$) in GGCX and a null mutation (@VARIANT$) in the @GENE$ gene, suggesting digenic nature of their skin findings.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"The @VARIANT$ mutation would be predicted to generate a nonfunctional DUOX1 enzyme, and its digenic inheritance alongside the homozygous @GENE$ @VARIANT$ will likely result in complete absence of functional DUOX isoenzyme in our patients. It has been speculated that @GENE$ upregulation in the context of DUOX2 loss of function may at least partially compensate for defective H2O2 production.",5587079,DUOX2;9689,DUOX1;68136,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"For example, patients 14 and 19 each carried one known truncating mutation (IVS28+1G>T) and a known inactivating mutation (p.R110Q or @VARIANT$). One showed severe CH and low intelligence level, and the other showed mild CH and normal intelligence. Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including @GENE$, @GENE$, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TPO;461,TG;2430,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Most had C9orf72 repeat expansion combined with another mutation (e.g. @GENE$ @VARIANT$ or TARDBP A321V; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in @GENE$ and A90V in TARDBP.",5445258,VCP;5168,ALS2;23264,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,0
"Out of the remaining 10 variants, 4 were detected in TANK-binding kinase 1 (TBK1), two in leucine rich repeat kinase 2 (@GENE$), one in optineurin (OPTN), one in fused in sarcoma (FUS), one in profilin 1 (PFN1) and one in the colony stimulating factor 1 receptor (@GENE$). Importantly, when we sorted these 10 remaining variants by pathogenicity score based on CADD_Phred score, all 4 TBK1 variants and the OPTN variant had scores higher than 20, meaning that those substitutions are predicted to be among the 1% most deleterious substitutions in the human genome (Table 1; Figure 1a). Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:@VARIANT$; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,LRRK2;18982,CSF1R;3817,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"(A) In addition to c.235delC in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Four genes (including AGXT2, @GENE$, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only @GENE$-@VARIANT$ (p.Ala1012Val) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,ZFHX3;21366,SCAP;8160,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"M4, PITX2: @VARIANT$. M5, PITX2: @VARIANT$. Arrows show the index cases. +: wild-type allele. The asterisk indicates a de novo PITX2 variant. Evolutionary conservation of @GENE$ and @GENE$ variants Evolutionary amino acid or nucleotide sequence conservation analysis were assessed using a multiple sequence alignment of representative orthologous proteins or genes of seven different species, from fish to human.",6338360,FOXC2;21091,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (@VARIANT$), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Mutations in NRXN1 and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, @VARIANT$) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"This included the variants in @GENE$ (chr6, NM_000426.3:@VARIANT$ (p.Thr127Ala); MAF 1.76 x 10-5) and @GENE$ (chr10, NM_0002211:c.1684_1686del (@VARIANT$); MAF 3.871 x 10-5), which affected amino acid residues that were found to be highly conserved across species (Fig. 1).",8474709,LAMA2;37306,LOXL4;12977,c.380A > G;tmVar:c|SUB|A|380|G;HGVS:c.380A>G;VariantGroup:0;CorrespondingGene:3908,p.Glu562del;tmVar:p|DEL|562|E;HGVS:p.562delE;VariantGroup:4;CorrespondingGene:84171,0
"    Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"In Family F, the @GENE$/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (c.965delA), @GENE$ (@VARIANT$) and C2orf74 (@VARIANT$) genes.",7877624,MITF;4892,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Pedigree and sequence chromatograms of the patient with the @VARIANT$ in @GENE$ and @VARIANT$ in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in MYO7A. Another variation, 158-1G>A in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0
"Low temperature incubation and salicylate treatment of cultured cells, which are thought to help with protein-folding processes, rescues the membrane localization of @VARIANT$. On the other hand, mis-localization of pendrin A372V from the plasma membrane is not restored by these treatments, suggesting these mutations may affect pendrin trafficking from the Golgi to the plasma membrane but not protein-folding. Here, we found that pendrin A372V, L445W, Q446R, and G672E did not bind to EphA2. Given the fact that loss of EphA2 disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of @GENE$ with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of pendrin from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with EphA2. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after @GENE$ stimulation.",7067772,pendrin;20132,ephrin-B2;3019,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"The proband in family PCG-139 also carried a rare PITX2 variant (@VARIANT$) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for @GENE$ and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, CYP1B1: @VARIANT$. M4, @GENE$: p.(P179T).",6338360,CYP1B1;68035,PITX2;55454,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"In the subject III.1, the variant, carried in the heterozygous status, is the c.868 G > T; @VARIANT$, in the @GENE$ (CGK) gene; the III.2 subject carried the @VARIANT$; p.Pro291Arg, in the @GENE$ gene.",8306687,glucokinase;55440,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be @GENE$, DFNB3, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES.",4998745,DFNB7/11;23670,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"GJB2 = gap junction protein beta 2, SNHL = sensorineural hearing loss, @GENE$ = wolfram syndrome 1.             Single Heterozygous GJB2 Mutant Allele Possibly Contributing to Deafness via Digenic Inheritance: Double Heterozygosity with Additional Mutation in Other Deafness Genes (Group II) Interestingly, two subjects (SH107-225 and SH175-389) showed double heterozygosity for a GJB2 mutation and another likely pathogenic mutation in another deafness gene. We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, @VARIANT$, in one of the c.235delC carriers (SH107-225) (Figure 4A). She inherited @VARIANT$ of GJB2 from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B).",4998745,WFS1;4380,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
"In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"The @VARIANT$ variant in @GENE$ occurring in complex heterozygosity with a pathogenic GJB3 variant, @VARIANT$ from SH175-389, suggests a possible digenic etiology of SNHL involving two different gap junction proteins, Cx26 and Cx31. Large deletions in @GENE$ (del [GJB6-D13S1830] and del [GJB6-D13S1854]) are frequently detected in a trans configuration with a monoallelic GJB2 mutation in certain populations.",4998745,GJB2;2975,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,PTK7;43672,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Prompted by the idea of an oligogenic mechanism of disease we further looked at the presence of more frequent variants (MAF <0.1%) in individuals already harboring extremely rare variants in @GENE$ and @GENE$ and noted that case A carrying the @VARIANT$ nonsense variant in OPTN, is compound heterozygote for mutations in OPTN as it also carries the rare variant @VARIANT$ (NM_001008211.1:c.1442C>T) in OPTN (MAF=0.0116% in ESP - CADD_Phred score: 34).",4470809,OPTN;11085,TBK1;22742,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Ala481Val;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). A compound heterozygous TEK mutation (p.E103D and p.E300G) was also observed in 1 family (PCG38). However, the remaining 20 PCG cases harboring a single heterozygous TEK mutation did not carry any additional mutation in the other 35 adult and childhood glaucoma-associated genes (Supplementary Fig. 1; Supplementary Table 1). The co-occurrence of heterozygous @GENE$ and @GENE$ mutations as seen in our PCG cases were not observed in additional sets of POAG, ARS, Aniridia, and Peter's Anomaly patients.",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,TOR2A;25260,ATP2A3;69131,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.R566L, p.@VARIANT$) vector plasmids and myc-tagged WT or mutant @GENE$ (p.R297C, @VARIANT$).",7279190,FLNB;37480,TTC26;11786,A2282T;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,1
"Furthermore, this @GENE$-Q1916R mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (p.R1193Q, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in @GENE$ was also found in the proband (Fig 2D, Table 2). This SCN5A-@VARIANT$ variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).    Gene variants of CACNA1C and SCN5A identified in the family. (A) Direct sequencing reveals a heterozygous mutation (c.5747A>G, p.Q1916R) in CACNA1C. (B) Amino acid sequencing alignments of CANCA1C indicate that @VARIANT$ is highly conserved across mammals (red font).",5426766,CACNA1C;55484,SCN5A;22738,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916;tmVar:Q1916;VariantGroup:8;CorrespondingGene:775,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,ENG;92,VEGFR2;55639,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
We identified a novel variant in the @GENE$ gene (c.@VARIANT$ p.K953E) and two already described missense variants in the @GENE$ gene (S159G and @VARIANT$).,3975370,NOD2;11156,IL10RA;1196,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, DVL3 @VARIANT$, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; p.Gln235*), and @GENE$ (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro.",4470809,OPTN;11085,TBK1;22742,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis.",3842385,WNT10A;22525,EDA;1896,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant @GENE$ loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.",5505202,WDR11;41229,EMX1;55799,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys).",8152424,DCC;21081,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,CAPN11;21392,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Except for the @GENE$ gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the @GENE$ gene variant [p.(@VARIANT$)].",8446458,SEMA7A;2678,DUSP6;55621,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD @VARIANT$ (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,KCNH2;201,SCN5A;22738,p.E1028V;tmVar:p|SUB|E|1028|V;HGVS:p.E1028V;VariantGroup:5;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.R566L, p.@VARIANT$) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$, p.R50C). Then, communoprecipitation assays were conducted. Western blot images are representative of n=3 experiments. AIS, adolescent idiopathic scoliosis; WT, wild type. To investigate the protein-protein interactions, we focused on AIS trios with multiple variants. We found that patients in two AIS trios (trios 22 and 27) carried variants in both the @GENE$ and TTC26 genes (figure 1).",7279190,TTC26;11786,FLNB;37480,A2282T;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Even the probands of the PCG188 and PCG200 families harboring the same @GENE$ (@VARIANT$)::@GENE$ (@VARIANT$) allelic combinations (Fig. 1a) had variable manifestations of IOP, corneal diameter, cup-to-disc ratio, and visual acuity at presentation.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"These results suggest an important role of ephrin-B2 as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of @GENE$.           Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin @VARIANT$, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin S166N was not internalized after ephrin-B2 stimulation while @GENE$ and other mutated pendrins were not affected.",7067772,ephrin-A1;3262,EphA2;20929,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
"The c.1787A>G (@VARIANT$) mutation of @GENE$ has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). The @VARIANT$ (p.Arg106Pro) variant of @GENE$, a rare single nucleotide polymorphism (SNP, rs544478083), has not yet been shown to be related to PFBC and is likely benign predicted by Mutation Taster, PolyPhen-2, and PROVEAN (data not shown).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,0
"Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of @VARIANT$ in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/MITF and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in @GENE$, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ @VARIANT$ and @GENE$ @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A).",5887939,CELSR1;7665,PRICKLE4;22752,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,1
"Sequence alterations were detected in the @GENE$ (rs144651558), RYR1 (@VARIANT$), CAPN3 (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,COL6A3;37917,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Notably, our patient's SOS1 variant, @VARIANT$, is three amino acids away from a well-documented class IB mutation p.Y337C, supporting the hypothesis that this novel @GENE$ variant is contributing to her phenotype. The @VARIANT$ mutation in @GENE$ has been associated with fetal macrosomia in one individual (Table I).",5101836,SOS1;4117,PTPN11;2122,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,0
"c, d Immunoprecipitation of @GENE$ with mutated @GENE$. Immunocomplex of myc-pendrin @VARIANT$, S166N and @VARIANT$ was not affected.",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Another candidate variant in MYH13 (@VARIANT$) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of @GENE$ is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: c.2059C>T, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs.",6081235,MYH13;55780,NOS2;55473,rs7807826;tmVar:rs7807826;VariantGroup:17;RS#:7807826,p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a @GENE$ (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father.",5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,1
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in MYO7A (p.K268R), but his brother, who is also clinically affected, does not carry the @GENE$ mutation. Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,MYO7A;219,USH2A;66151,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"Our results indicate that the novel KCNH2-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas @GENE$-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNE1;3753,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"In the second family, we identified a heterozygous @VARIANT$ mutation in @GENE$, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a @GENE$ variant (@VARIANT$) was involved in 18 pathogenic digenic combinations.",8446458,PROKR2;16368,CCDC141;52149,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (@VARIANT$)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (@VARIANT$) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"This indicates that neither p.R143W in @GENE$ nor p.D771N in WFS1 contributed to SNHL in SH60-136 and that @VARIANT$ in GJB2 was an incidentally detected variant in this subject. GJB2 = gap junction protein beta 2, SNHL = sensorineural hearing loss, WFS1 = wolfram syndrome 1.             Single Heterozygous GJB2 Mutant Allele Possibly Contributing to Deafness via Digenic Inheritance: Double Heterozygosity with Additional Mutation in Other Deafness Genes (Group II) Interestingly, two subjects (SH107-225 and SH175-389) showed double heterozygosity for a GJB2 mutation and another likely pathogenic mutation in another deafness gene. We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, p.R341C, in one of the c.235delC carriers (SH107-225) (Figure 4A). She inherited c.235delC of GJB2 from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). The @VARIANT$ residue of MITF is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C).",4998745,GJB2;2975,MITF;4892,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,ANG;74385,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"   The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane.",7067772,EphA2;20929,pendrin;20132,Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,1
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the SLC20A2 mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"    To further determine the function of the c.971T>C (p.Ile324Thr) SARS variant, sars morphants were coinjected with WT and @VARIANT$ mutant human mRNA. Intriguingly, coinjection of human SARS WT mRNA, but not the SARS mutant [c.971T>C] mRNA, rescued the BAVM-like phenotype in sars morphants (figure 2B, online supplementary videos 7-8), as indicated by a decreased proportion of embryos with brain vessel abnormalities (figure 2D), thus identifying c.971T>C (p.Ile324Thr) in SARS as a pathogenic variant. sars encodes a seryl-transfer RNA synthetase, but this enzymatic function is dispensable for its role in vascular development. The mutation we identified falls near the L-serine binding site (p.325Glu) of SARS, but how it affects @GENE$ non-canonical activity in vascular development remains to be determined (as does whether this mutation affects Sars seryl-tRNA synthetase activity).  The de novo heterozygous missense variant c.2636C>G (@VARIANT$) in @GENE$ (pLI=1) was identified in patient AVM334 (table 1).",6161649,SARS;4751,LEMD3;8633,c.971T>C;tmVar:c|SUB|T|971|C;HGVS:c.971T>C;VariantGroup:11;CorrespondingGene:54756;RS#:145221454;CA#:143831,p.Thr879Ser;tmVar:p|SUB|T|879|S;HGVS:p.T879S;VariantGroup:9;CorrespondingGene:57758;RS#:765732511,0
"(A) In addition to c.235delC in GJB2, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of @GENE$ and a monoallelic p.A194T variant of GJB3.",4998745,MITF;4892,GJB2;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
The p.(@VARIANT$) mutation was predicted to be highly destabilizing. (B) Alignment of P3B3 domain (a.a. 750-787 of human LRP6). The Alanine754 is extremely conserved among orthologs of @GENE$ and @GENE$. The p.(@VARIANT$) mutation was predicted to be highly destabilizing.,8621929,LRP6;1747,LRP5;1746,Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Protein structure analysis We performed protein structure analysis on the two WNT10A mutations (@VARIANT$ and p.G213S) and two novel @GENE$ mutations (p.G257R and @VARIANT$) that were identified in this study. For @GENE$, the conservation of residues in sequences was determined to predict the influence of the two mutations.",3842385,EDA;1896,WNT10A;22525,p.R171C;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.I312M;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"We observed that recombinant @GENE$ and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (@VARIANT$) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-@VARIANT$, KCNH2-@VARIANT$, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,0
"The @VARIANT$ (@VARIANT$) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between @GENE$ and @GENE$ has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).",7549550,RIPPLY1;138181,MYOD1;7857,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,1
The @GENE$-p.R583H variant was previously reported to be associated with LQTS; KCNH2-@VARIANT$ is a novel variant; and KCNH2-p.K897T and @GENE$-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels.,5578023,KCNQ1;85014,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (p.R559W) and PKHD1: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).          Whole-exome sequencing revealed that the foetal PKD proband in Family 23 had compound heterozygous variants in PKHD1, which was subsequently verified through Sanger sequencing. The mother and the father were asymptomatic carriers of @GENE$: c.4437_4440delCATA (@VARIANT$) and PKHD1: c.5935G > A (p.G1979R), respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,p.F1479Lfs*20;tmVar:p|FS|F|1479|L|20;HGVS:p.F1479LfsX20;VariantGroup:43;CorrespondingGene:5314,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"For HH12, the molecular analysis allowed the identification of a novel variation, @VARIANT$; p.(Lys205del), in the PROKR2 gene at a heterozygous state. Bioinformatics analysis using the Uniprot database showed that the @VARIANT$ is buried amid the second extracellular loop and that this residue is highly conserved in @GENE$ from mouse, rat, chimp, dog, cow, Xenopus tropicalis, and zebrafish and in the human @GENE$ protein.",8446458,Prokr2;16368,PROKR1;10968,c.614_616del;tmVar:c|DEL|614_616|;HGVS:c.614_616del;VariantGroup:16;CorrespondingGene:128674,lysine amino acid at position 205;tmVar:|Allele|LYSINEAMINO|205;VariantGroup:11;CorrespondingGene:6939,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (@GENE$) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1.",4470809,OPTN;11085,TANK-binding kinase 1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT5;71688,LQT2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and C104R (@VARIANT$) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The functional consequence of KCNH2-@VARIANT$ was investigated by analyzing the ionic currents from cells expressing KCNH2-WT or KCNH2-p.C108Y and from cells co-expressing both alleles. 2.3.1. Functional Effects of KCNQ1-@VARIANT$ The expression of KCNQ1-p.R583H in CHO-K1 cells evoked robust outward currents, and no significant differences in activating and tail current densities were identified between cells expressing a @GENE$-p.R583H channel and cells expressing a KCNQ1-WT channel. However, there was a statistically significant positive shift in the voltage-dependence of activation (V1/2: @GENE$-WT, -21.1 +- 0.86 mV, n = 13; KCNQ1-p.R583H, -16.7 +- 1.22 mV, n = 11, p < 0.05) without a significant alteration in the slope factor (k: KCNQ1-WT, 3.5 +- 0.7 mV, n = 13; KCNQ1-p.R583H, 4.6 +- 1.2 mV, n = 11, p > 0.05).",5578023,KCNQ1;100761481,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
      Variant screening The @GENE$ (@VARIANT$) and @GENE$ (@VARIANT$) variants were validated and investigated in additional family members by using Sanger sequencing of PCR products obtained under standard PCR conditions.,7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,1
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and @VARIANT$ pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,1
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,CCNF;1335,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of @GENE$ and a monoallelic p.A194T variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Variant in TYRO3 (c.1037T>A; @VARIANT$) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, LRP4, @GENE$, LRP6, ROR1, @GENE$, GSK3, CK1, APC, BCL9, and BCL9L) as well. No potentially pathogenic rare variant was identified. In order to identify variant(s) in other genes which might influence the expressivity of WS phenotype in our cases, exome data was filtered by using an unbiased and hypothesis-free approach. A rare missense variant (@VARIANT$; p.Val34Gly) in the C2orf74 gene was identified in both affected individuals.",7877624,LRP5;1746,ROR2;55831,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"          Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/@GENE$ regulation. a, b Immunoprecipitation of EphA2 with mutated @GENE$. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected.",7067772,ephrin-B2;3019,pendrin;20132,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including @GENE$ may modulate the WS2 phenotype in WS2 cases with MITF mutation.",7877624,EDNRB;89,LEF-1;7813,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
Most had @GENE$ repeat expansion combined with another mutation (e.g. VCP @VARIANT$ or @GENE$ @VARIANT$; Supplementary Table 6).,5445258,C9orf72;10137,TARDBP;7221,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,A321V;tmVar:p|SUB|A|321|V;HGVS:p.A321V;VariantGroup:27;CorrespondingGene:23435,0
"One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,CELSR2;1078,FAT4;14377,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"For example, patients 14 and 19 each carried one known truncating mutation (IVS28+1G>T) and a known inactivating mutation (@VARIANT$ or p.R885Q). One showed severe CH and low intelligence level, and the other showed mild CH and normal intelligence. Similarly, patients 8 and 10 both had a combination of a known truncating mutation (@VARIANT$) and a known inactivating mutation (p.R110Q or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, TG, DUOX2, @GENE$, @GENE$, SCL5A5, and IYD, have been detected in numerous cases.",6098846,DUOXA2;57037,SLC26A4;20132,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,UNC13B;31376,SPTBN4;11879,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"(A) Segregation of the @GENE$-p.R583H, KCNH2-p.C108Y, @GENE$-@VARIANT$, and KCNE1-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNQ1;85014,KCNH2;201,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"In our study, @VARIANT$(p. Arg631*) and c.1267C > T(p. Arg423*) were the two reported variants, while c.1525delA(p. Ser509fs) and c.1524del A(@VARIANT$) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of @GENE$ gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function.         Prokineticin-2 (PROK2) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the PROKR2 and PROKR2 genes, which can be passed down through autosomal dominant or oligogenic inheritance. In our study, 40% of patients developed PROK2/@GENE$ variants, which was significantly higher than the 9% in the Caucasian population.",8796337,KAl1;55445,PROKR2;16368,c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223,p. Ser509fs;tmVar:p|FS|S|509||;HGVS:p.S509fsX;VariantGroup:19;CorrespondingGene:3730,0
"  Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a @GENE$ homozygous nonsense mutation (@VARIANT$); P1, P2: thyrotropin >100 microU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous @GENE$ mutation (@VARIANT$) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred.",5587079,DUOX2;9689,DUOX1;68136,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,1
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and @GENE$ p.R408C with SETX p.I2547T and SETX @VARIANT$).,4293318,VAPB;36163,TAF15;131088,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD.  Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.2857A > G @VARIANT$) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.@VARIANT$ p.G351R), have already been described in the literature.",3975370,IL10RA;1196,IL10RB;523,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,1051 G > A;tmVar:c|SUB|G|1051|A;HGVS:c.1051G>A;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Somatic overgrowth associated with homozygous mutations in both @GENE$ and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ @VARIANT$ (p.M400I) and MAN1B1 @VARIANT$ (p.R334C), associated with congenital birth defects in two patients from a consanguineous family.",4853519,MAN1B1;5230,SEC23A;4642,c.1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"  Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a @GENE$ homozygous nonsense mutation (@VARIANT$); P1, P2: thyrotropin >100 microU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (@VARIANT$) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred. Conclusion: This is a report of digenic mutations in @GENE$ and DUOX2 in association with CH, and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype.",5587079,DUOX2;9689,DUOX1;68136,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"We finally found evidence of four potential novel candidate genes contributing to IHH: coiled-coil domain containing 88C (CCDC88C), cell adhesion associated, oncogene regulated (@GENE$), glutamate decarboxylase like 1 (GADL1), and sprouty related EVH1 domain containing 3 (SPRED3). The @GENE$ missense variant p. Arg1299Cys was heterozygous in case P05. CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant @VARIANT$ was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,CDON;22996,CCDC88C;18903,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,SPTBN4;11879,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"We suggest that: 1) the PKD2 p.(Cys331Thr) variant is pathogenic, since it is de-novo in a patient with a renal cystic disease and is transmitted to both fetuses; 2) the p.(@VARIANT$) variant in PKD1 is hypomorphic, since it does not cause renal disease in the father (age 44 years), but worsens the renal phenotype when co-inherited with a PKD2 mutation; 3) the missense variant p.(@VARIANT$) in PKD2, already described as disease-causing in HGMD database (Neumann et al.,), is likely benign, since it is present in a healthy man and does not segregate with disease in the fetuses. Pedigree of Family 18287 with bilineal inheritance of @GENE$/@GENE$ variants.",7224062,PKD1;250,PKD2;20104,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and @GENE$/TACI C104R mutations. Other family members who have inherited @GENE$ T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited @GENE$ T168fsX191 and @GENE$/TACI C104R mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, @VARIANT$, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 @VARIANT$, @GENE$ @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of @GENE$, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,PTK7;43672,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) GBE1 R524Ter; 2) @GENE$ G407RfrTer14; 3) @GENE$ IVS8DC; 4) OAT @VARIANT$. Two additional variants, @VARIANT$ in RYR1 and p. R498L in CACNA1S, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,PCCB;447,NUBPL;11854,"Y299Ter;tmVar:p|SUB|Y|299,ER|T;HGVS:p.Y299,ERT;VariantGroup:10;CorrespondingGene:4942",p. T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,0
"Notably, the @VARIANT$ residue of @GENE$, and the @VARIANT$ and C3307 residues of @GENE$, which are involved in the USH patients' missense mutations, are conserved in C. savignyi.",3125325,myosin VIIa;219,usherin;66151,P1220;tmVar:P1220;VariantGroup:299;CorrespondingGene:4647,G1301;tmVar:c|Allele|G|1301;VariantGroup:17;CorrespondingGene:7399;RS#:111033524,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and @GENE$ and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated @GENE$ mutation (c.1403 C > T; @VARIANT$) and a novel, potentially pathogenic missense SOS1 variant (@VARIANT$; p.P340S) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,neurofibromatosis 1;226,PTPN11;2122,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,c.1018 C > T;tmVar:c|SUB|C|1018|T;HGVS:c.1018C>T;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,CAPN11;21392,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes.     ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The p.Ala349Thr (@VARIANT$) mutation in exon 9 of @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of WNT10A were detected.",3842385,WNT10A;22525,EDA;1896,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  @GENE$, 23  @GENE$, 24  and CAPN9. 25  The RYR3 (NM_001036: @VARIANT$, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,EBNA1BP2;4969,TRIP6;37757,c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, @VARIANT$ or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of @GENE$ function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin F355L mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (@VARIANT$) in MFSD8. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (EHMT1 c.1513G > A at a rate of 4.95 x 10-5, @GENE$ c. 353A > G at a rate of 8.24 x 10-6).",7463850,EHMT1;11698,MFSD8;115814,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ p.R769W, DVL3 @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB @VARIANT$) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,CELSR1;7665,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The genotypes of SLC20A2 (NM_001257180.2: c.1787A>G, @VARIANT$) and @GENE$ (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding PDGFRB, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"We identified four genetic variants (KCNQ1-@VARIANT$, KCNH2-p.C108Y, @GENE$-p.K897T, and @GENE$-@VARIANT$) in an LQTS family.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"However, we obtained a positive response in the initial assays carried out to set up the functional evaluation of @GENE$, and we decided to use this promoter in further experiments. The results showed that the two @GENE$ variants @VARIANT$ and @VARIANT$ were associated with a 22%-28% reduced transactivation (Fig 5A).",6338360,PITX2;55454,FOXC2;21091,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,0
"NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and c.850C>T (@VARIANT$) in @GENE$ and SGCA genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in ANO5 gene and one pathogenic variant in @GENE$ gene indicating multiple gene contributions for an unusual presentation.",6292381,ANO5;100071,COL6A2;1392,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,R284C;tmVar:p|SUB|R|284|C;HGVS:p.R284C;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, @GENE$, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,SNAI3;8500,RNF43;37742,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the @GENE$ gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Three of these individuals were heterozygous, but none was homozygous for @VARIANT$. Sequencing of the @GENE$ intronic and 5'-flanking sequences was performed in the affected patients and no other variants were identified (data not shown). The novel truncated variant in @GENE$ was not found in our ""in-house"" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The c.229C>T (p.R77C) variant in S100A3 and c.238-241delATTG (@VARIANT$) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.",6637284,S100A3;2223,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON @VARIANT$ variants from his unaffected father and mother, respectively.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the @GENE$ and @GENE$ proteins lead us to hypothesize that digenic variants in NRXN1 and NRXN2 contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,UBQLN2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates                TOR2A missense variant A TOR2A nonsynonymous SNV (c.568C>T [NM_130459.3], @VARIANT$ [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,REEP4;11888,BSP+;3644,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"The result indicated that @GENE$ @VARIANT$ might impact the catalytic efficiency of protein. However, there was no significant change in protein phosphorylation for @GENE$ @VARIANT$ (Table 4).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Moreover, the presence of other variants (@GENE$-p.R583H, @GENE$-@VARIANT$, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNH2;201,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"The DNA sequencing chromatograms from the proband show two @GENE$ and one WNT10A heterozygous mutations. While both LRP6 variants, p.(@VARIANT$) and p.(Asn1075Ser), were inherited from her father, the @GENE$ mutation, @VARIANT$ was maternally derived.",8621929,LRP6;1747,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"To the best of our knowledge, two of the identified variants (FOXC2: @VARIANT$, p.(H395N); and PITX2: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and p.(H395N); PITX2: @VARIANT$). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (@VARIANT$ of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,TACR3;824,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A3;2223,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB p.M170I and @GENE$ p.R408C with @GENE$ p.I2547T and SETX @VARIANT$).,4293318,TAF15;131088,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, @VARIANT$), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of @GENE$ and SCN5A genes are closely related to LQTS.",8739608,LAMA2;37306,KCNH2;201,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"    Results We identified the digenic heterozygous mutations of KCNH2 p.307_308del (NM_001204798, c.921_923del) and SCN5A @VARIANT$ (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. Subsequently, she occurred with obvious sinus arrest with persistent ventricular pacing of implantable cardioverter-defibrillator. The heterozygous SCN5Ap.R1865H was carried by her father and sister but not carried by I:2. II:1 carried with KCNH2 @VARIANT$ as a de novo mutation, but not existed in other family members. RNA secondary structure of KCNH2 p.307_308del showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Nav1.5 protein property, @GENE$ p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index.   Conclusions The digenic heterozygous @GENE$ and SCN5A mutations were associated with young early-onset long QT syndrome and sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB @VARIANT$, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Intriguingly, parents of the PCG-affected children who carried a single copy of the @GENE$ or CYP1B1 mutant allele were asymptomatic, suggesting that the heterozygous variations by themselves were not pathogenic.    Interaction of TEK and CYP1B1 As the identified allelic combinations were extremely rare in our cohort, we carried out in vitro analysis to determine biochemical interaction between these proteins. First, we tested if TEK and CYP1B1 could physically interact with each other. Co-transfection of HEK293 (human embryonic kidney) cells with plasmids encoding recombinant HA-TEK (hemagglutinin-tagged TEK) and GFP-CYP1B1 followed by co-immunoprecipitation with anti-GFP-conjugated beads demonstrated that HA-TEK and GFP-@GENE$ are part of the same complex. As negative control, no interaction was detected between the GFP tag and HA-TEK proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 @VARIANT$ and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished.",5953556,TEK;397,CYP1B1;68035,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (@VARIANT$ of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,TACR3;824,NELF;10648,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: p.(C498R) and @VARIANT$; PITX2: @VARIANT$). In summary, the increased frequency in PCG patients of rare FOXC2 and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and @GENE$ @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,CELSR1;7665,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in @GENE$ and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MYOD1;7857,TBX6;3389,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant.",8152424,CDON;22996,FGFR1;69065,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We provide evidence that mutations in the Cx26 and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Because charged residues are important for proteins trafficking, the A194T may result in accumulation of the @GENE$ protein in intracellular compartments such as the Golgi apparatus or in other sites such as the endoplasmic reticulum or lysosomes. The A194T substitution might cause conformational changes within the Cx31 molecule or affect the ability of Cx31 to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the Cx26 mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in @GENE$ underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to @VARIANT$ and A194 identified in the families reported here, namely, @VARIANT$, R165W, F191L, and A197S in Cx26 as well as F193C, S198F and G199R in Cx32, have been reported previously in patients with hearing impairment.",2737700,Cx31;7338,Cx32;137,N166;tmVar:p|Allele|N|166;VariantGroup:0;CorrespondingGene:2707;RS#:121908851,M163L;tmVar:p|SUB|M|163|L;HGVS:p.M163L;VariantGroup:7;CorrespondingGene:2706;RS#:80338949,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of @GENE$ and C104R (c.310T>C) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Out of the remaining 10 variants, 4 were detected in TANK-binding kinase 1 (TBK1), two in leucine rich repeat kinase 2 (LRRK2), one in optineurin (OPTN), one in fused in sarcoma (FUS), one in profilin 1 (PFN1) and one in the @GENE$ (CSF1R). Importantly, when we sorted these 10 remaining variants by pathogenicity score based on CADD_Phred score, all 4 TBK1 variants and the OPTN variant had scores higher than 20, meaning that those substitutions are predicted to be among the 1% most deleterious substitutions in the human genome (Table 1; Figure 1a). Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; p.Gln235*), and @GENE$ (NM_013254.3:@VARIANT$; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,colony stimulating factor 1 receptor;3817,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,0
"These mutations are expected to affect the three classes of @GENE$ isoforms (Tables 2, 3, Figure 1). Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A), a novel nucleotide deletion (c.6404_6405delAG; p.E2135fsX31), and six missense mutations, four of which (p.R1189W, @VARIANT$, p.D2639G, and @VARIANT$) had not been previously reported.",3125325,harmonin;77476,CDH23;11142,p.R1379P;tmVar:p|SUB|R|1379|P;HGVS:p.R1379P;VariantGroup:93;CorrespondingGene:286;RS#:748160803;CA#:4727654,p.R3043W;tmVar:p|SUB|R|3043|W;HGVS:p.R3043W;VariantGroup:141;CorrespondingGene:64072;RS#:375907609;CA#:5546888,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in @GENE$. Another variation, @VARIANT$ in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,1
"In the subject III.1, the variant, carried in the heterozygous status, is the c.868 G > T; @VARIANT$, in the glucokinase (@GENE$) gene; the III.2 subject carried the c.872 C > G; @VARIANT$, in the @GENE$ gene.",8306687,CGK;55964,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,1
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (@GENE$), previously seen in controls (@GENE$), or when identified in a family, did not segregate with the disease (FUS).",4470809,CSF1R;3817,PFN1;3684,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and @VARIANT$ (R284C) in @GENE$ and @GENE$ genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in ANO5 gene and one pathogenic variant in COL6A2 gene indicating multiple gene contributions for an unusual presentation.",6292381,ANO5;100071,SGCA;9,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"KCNH2 p.307_308del and @GENE$ p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A p.R1865H. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of @GENE$ @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus lead to a reduction of structural stability. However, SCN5A p.R1865H showed no significant influence on the RNA structure (Figure 4c,d). The MFE of SCN5A @VARIANT$ mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and @GENE$ (c.9921T>G).",3125325,CDH23;11142,USH2A;66151,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with VAPB @VARIANT$ and @GENE$ @VARIANT$ with SETX p.I2547T and SETX p.T14I).,4293318,ANG;74385,TAF15;131088,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes @VARIANT$, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/@VARIANT$ (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,0
"However, when combined with the @GENE$ mutations, it led to a severe phenotype of thirteen missing teeth in the proband. This genetic synergism is also supported by the potential digenic inheritance of LRP6 and WNT10A mutations in Family 4. The proband, who had LRP6 p.(@VARIANT$), p.(Ser127Thr), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Biallelic pathogenic variants in the TMEM67 gene may lead to @GENE$, with overlapping symptoms to ADPKD, including renal cysts and central nervous dysplasia, among which the latter was not evidently manifested in Family 24. One possible explanation for this could be that @VARIANT$ (@VARIANT$) was possibly a hypomorphic variant. 47  The @GENE$ gene is expressed in a subset of embryonic tissues 48  and is involved in cilia formation.",8256360,MKS3;71886,TMEM107;12052,c.637C > T;tmVar:c|SUB|C|637|T;HGVS:c.637C>T;VariantGroup:3;CorrespondingGene:5314;RS#:866575098;CA#:138924774,p.R213C;tmVar:p|SUB|R|213|C;HGVS:p.R213C;VariantGroup:3;CorrespondingGene:91147;RS#:866575098,0
"Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in EHMT1 and c.353A > G (@VARIANT$) in MFSD8. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (@GENE$ c.1513G > A at a rate of 4.95 x 10-5, MFSD8 c. 353A > G at a rate of 8.24 x 10-6).",7463850,SLC9A6;55971,EHMT1;11698,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,TACR3;824,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,FUS;2521,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,KAL1;55445,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"In two unrelated patients, AVM106 and AVM285, identical compound heterozygous variants were identified in @GENE$: c.5783G>A (p.Arg1928His) and c.4574G>A (p.Arg1525His), each inherited from heterozygous carrier parents (table 2). Both variants were reported in ExAC with an allele frequency <0.001, and they were predicted in silico to be highly deleterious (GERP++>4 and CADD>30 for both). In patient AVM226, we identified the compound heterozygous variants @VARIANT$ (p.Val1259Ile) and c.2966A>T (p.Gln989Leu) in DSCAM (table 2). DSCAML1 and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in PTPN13 (table 2).",6161649,DSCAML1;79549,DSCAM;74393,c.3775G>A;tmVar:c|SUB|G|3775|A;HGVS:c.3775G>A;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"          Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the @GENE$ and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a valine by methionine at position 255 (@VARIANT$) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b).",2900916,GGCX;639,VKORC1;11416,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ @VARIANT$ and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A).",5887939,CELSR1;7665,SCRIB;44228,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; @VARIANT$] variants which displayed digenic inheritance (Fig. 1a).                   The @GENE$ variant [NM_033056: c.3101G > A; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892).",6053831,USH1G;56113,PCDH15;23401,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,p.(Asp365Asn);tmVar:p|SUB|D|365|N;HGVS:p.D365N;VariantGroup:1;CorrespondingGene:124590;RS#:538983393;CA#:8753931,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), @VARIANT$ (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,Ser166 to Asn;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"@GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,DFNB1;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in MYO7A (p.K268R), but his brother, who is also clinically affected, does not carry the @GENE$ mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), @GENE$ (c.46C>G; p.L16V) and USH2A (@VARIANT$).",3125325,MYO7A;219,USH1G;56113,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"We found that @GENE$ variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described @VARIANT$ mutant. By contrast, GATA4 variants @VARIANT$ and Pro226Leu activated the @GENE$ promoter similar to wt.",5893726,GATA4;1551,CYP17;73875,Gly221Arg;tmVar:p|SUB|G|221|R;HGVS:p.G221R;VariantGroup:4;CorrespondingGene:2626;RS#:398122402(Expired),Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"Interestingly, it has been reported that the @GENE$-@VARIANT$ variant, located in the PAS domain, reaches the cell surface, but it remains in the immature form and is non-conducting. On the contrary, the functionality of the @GENE$-@VARIANT$ channels was not severely compromised in a manner typical of LQTS-associated mutations.",5578023,KCNH2;201,KCNQ1;85014,p.C66G;tmVar:p|SUB|C|66|G;HGVS:p.C66G;VariantGroup:2;CorrespondingGene:3757;RS#:199473416;CA#:6132,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, CDH23 and @GENE$ in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for @GENE$ , 11%-15% for PCDH15 , and for USH2A in USH2 patients, whereas the implication of VLGR1 and WHRN in the latter was minor.",3125325,PCDH15;23401,CDH23;11142,c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"(b) A sequence chromatogram showing the @GENE$ (c.253C>T;@VARIANT$) mutation. (c) A sequence chromatogram showing the @GENE$ (c.1306A>G;p.I436V) mutation. In the chromatograms, mutations are indicated with arrows. Mutagenesis The full-length WDR11 complementary DNA in pcDNA-green fluorescent protein (GFP) or pcDEST-Myc vector was mutagenized by using a Q5 site-directed mutagenesis kit (New England BioLabs, Ipswich, MA) to introduce the @VARIANT$ variant, following the manufacturer's protocol.",5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,REEP4;11888,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 @VARIANT$, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, @VARIANT$ located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,CELSR1;7665,SCRIB;44228,p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"                                    Tumor analysis MMR deficiency in tumor samples was assessed by microsatellite instability analysis and immunohistochemical detection of the four MMR proteins (MLH1, MSH2, @GENE$, and @GENE$). 11  KRAS codon 12/13 mutations were screened with Sanger sequencing. 12   Functional MMR assay In vitro MMR activity assay was performed as previously described. 13   RESULTS We performed germline whole-exome sequencing on three CRC patients diagnosed before 60 years of age (III-1, III-7, III-8, Figure 1A) and who belonged to a CRC family comprising of seven cancer patients divided over two generations. Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: @VARIANT$, p.Thr1100Met) and MUTYH (NM_001128425.1: @VARIANT$, p.Tyr179Cys) genes, while the other 20 genes could not be clearly linked to cancer predisposition.",7689793,MSH6;149,PMS2;133560,c.3299C > T;tmVar:c|SUB|C|3299|T;HGVS:c.3299C>T;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.536A > G;tmVar:c|SUB|A|536|G;HGVS:c.536A>G;VariantGroup:15;CorrespondingGene:4595;RS#:145090475;CA#:7607273,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"His cells produced higher levels of IgG and IgM than his mother (II.2, who bears both the TNFRSF13B/@GENE$ @VARIANT$ and @GENE$ @VARIANT$ mutations).",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1
"Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (@VARIANT$) in the @GENE$ gene. Moreover, a rare heterozygous, missense damaging variant (c.101T>G; @VARIANT$) in the @GENE$ has also been identified.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,ENG;92,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,0
"Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, @GENE$ (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant p. Val969Ile of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. CDON seems to act similarly as @GENE$ through a digenic/oligogenic model to contribute to IHH.",8152424,tachykinin receptor 3;824,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"The @GENE$-c.G112A (p.G38S) variant has been reported to reduce KCNH2 and KCNQ1 channel currents, enhance KCNH2 susceptibility to QT-prolonging factors, and increase the risk for LQTS, atrial fibrillation, and heart failure. Bioinformatic analysis predicted that KCNE1-G38S was ""tolerated"" and KCNH2-C108Y was ""damaging"", whereas divergent results were obtained for KCNQ1-R583H and KCNH2-K897T, i.e., some programs considered these variants ""damaging"" and others as ""benign"" (Table 2). Moreover, the MAF of KCNQ1-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of @GENE$-p.K897T and KCNE1-p.G38S were much larger (0.187 and 0.352, respectively). KCNH2-p.@VARIANT$ is not reported in the ExAC database.",5578023,KCNE1;3753,KCNH2;201,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue TCF3 @VARIANT$ mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the @GENE$/TACI C104R mutation.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Both sisters inherited the HNF4A gene mutation R127W from their mother and the @GENE$ gene mutation P291fsinsC (@VARIANT$) from their father. The father was diagnosed with diabetes at 45 years of age. Their brother is heterozygous for the @GENE$ @VARIANT$ mutation.,4090307,HNF1A;459,HNF4A;395,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"Subsequently many genes encoding folate pathway enzymes, transporters and receptors have been studied with mostly inconsistent findings.7 More recently, several candidate variants were identified in AMT and GLDC, 2 of the genes constituting the mitochondrial GCS.10, 32 In the present study, we identified a novel missense variant affecting the catalytic domain of the @GENE$ gene. This patient additionally carried the @VARIANT$ variant, and a rare missense variant (@VARIANT$) in the @GENE$ gene.",5887939,MTHFR;4349,GLDC;141,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332,1
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (c.229C>T; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.    Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, @VARIANT$ in @GENE$ and rs138355706 in S100A3, and one novel variant in @GENE$, were identified.",6637284,SETDB1;32157,S100A13;7523,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The p.Ala349Thr (@VARIANT$) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of @GENE$ were detected. These mutations were not found in his father's genome, but because his mother's DNA sample was unavailable, the origin of the mutant alleles was not clear (Fig. 2F).     All novel mutations that were identified in this study were not found in the normal controls. Protein structure analysis The results of protein structure analyses of WNT10A are shown in Figure 3. R171 and @VARIANT$ are conserved residues through these organisms and located on conserved 2D fragments.",3842385,EDA;1896,WNT10A;22525,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216,0
"21  Additional gene reportedly linked to tumorigenesis include @GENE$, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, @VARIANT$) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25  The contribution of the genetic variants, other than @GENE$ and MUTYH, to cancer risk cannot be completely excluded.",7689793,RYR3;68151,MSH6;149,p.Asn2604Lys;tmVar:p|SUB|N|2604|K;HGVS:p.N2604K;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The loss-of-function variation in SCN5A or CACNA1C (e.g., @GENE$-@VARIANT$), which produces inadequate inward hybrid currents, is responsible for the pathopoiesis of ERS. Thus, from the mechanistic point of view, INa and ICa-L show a synergistic effect on the repolarization as two ingredients of the inward currents. In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental CACNA1C-Q1916R mutation might be partly compensated by the persistent inward tail INa produced by the @GENE$-@VARIANT$ channel.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 @VARIANT$, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,CDON;22996,FGFR1;69065,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"M2, @GENE$: @VARIANT$. M3, CYP1B1: p.(E173*). M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"In addition, 2 genes presented variants in 3 patients: MAML3 (patients 6, 7 and 8) and @GENE$ (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in  Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, @GENE$, FGF10, RET, PROP1 and NRP1.",6726737,NOTCH1;32049,GLI2/3;2736;2737,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,FUS;2521,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"Four genes (including AGXT2, ZFHX3, SCAP, @GENE$) were found to be related to the PMI related. It turned out to be that only @GENE$-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,TCF4;2407,SCAP;8160,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"Both SSPIDER and INTERPROSURF analysis (Figure S4) suggest functional importance for Ala253; and SIFT predicts a deleterious effect for @VARIANT$. Although p.Ala253Thr did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, @GENE$, @GENE$, GNRHR, GNRH1, or KISS1R.",3888818,TAC3;7560,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Proband 17 inherited @GENE$ @VARIANT$ and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively.",8152424,CHD7;19067,CDON;22996,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,1
"The Alanine754 is extremely conserved among orthologs of LRP6 and @GENE$. The p.(@VARIANT$) mutation was predicted to be highly destabilizing. (C) Alignment of P4B3 domain (a.a. 1059-1097 of human @GENE$). While @VARIANT$ is highly conserved among orthologs of LRP6 and LRP5, zebrafish LRP5 and Drosophila Arrow use threonine and aspartate, respectively, at this position.",8621929,LRP5;1746,LRP6;1747,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Asparagine1075;tmVar:p|Allele|N|1075;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and @VARIANT$; (B) in the NOD2 exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,R351G;tmVar:p|SUB|R|351|G;HGVS:p.R351G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The LRP6 @VARIANT$ mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,LRP6;1747,WNT10A;22525,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"In our study, we identified four genetic variants in three genes (KCNQ1-@VARIANT$, @GENE$-p.C108Y, KCNH2-p.K897T, and @GENE$-@VARIANT$).",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,1
"        Molecular Data All three probands carry two heterozygous variants: SQSTM1, c.1175C>T (@VARIANT$), and @GENE$, @VARIANT$ (p.Asn357Ser). None of the unaffected family members harbor both variants (Figure 1). The TIA1 variant and @GENE$ variants have been reported in multiple databases.",5868303,TIA1;20692,SQSTM1;31202,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant p.A2282T and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the @VARIANT$ residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the @GENE$ mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078.",7279190,TTC26;11786,FLNB;37480,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,R2003;tmVar:R2003;VariantGroup:29;CorrespondingGene:2317,0
Our USH1 patient (Case #4) had segregated @GENE$:@VARIANT$ and @GENE$:@VARIANT$. Molecular analyses in mouse models have shown many interactions among the USH1 proteins.,3949687,MYO7A;219,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,1
"Two novel variants of the @GENE$ gene were found in patients with anosmia, obvious small phallus, and low levels of sex hormones. c.223 - 4C > A might affect the normal splicing of exons in the PROK2 gene, and the novel variant @VARIANT$ (p. Arg102Ser) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a PROK2 gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the @GENE$ gene were found in eight patients. c.337 T > C (p. Tyr113His) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. @VARIANT$ (p. Arg164Gln) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors.",8796337,PROK2;9268,PROKR2;16368,c.306G > C;tmVar:c|SUB|G|306|C;HGVS:c.306G>C;VariantGroup:27;CorrespondingGene:60675,c.491G > A;tmVar:c|SUB|G|491|A;HGVS:c.491G>A;VariantGroup:3;CorrespondingGene:128674;RS#:751875578;CA#:311167332,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (@GENE$) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,OPTN;11085,TBK1;22742,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Proband 17 inherited @GENE$ @VARIANT$ and CDON @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant.",8152424,CHD7;19067,FGFR1;69065,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, @VARIANT$), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,TOR2A;25260,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Notably, our study has revealed one case of likely oligogenic inheritance for USH1, involving MYO7A and USH1G, and possibly @GENE$. Three cases of digenic inheritance of USH1 have been reported so far, all caused by mutations in CDH23 and PCDH15, in agreement with the contribution of cadherin-23 and @GENE$ to the hair bundle transient lateral links and tip-links. The pathogenicity of the p.T1209A mutation in CDH23  is, however, questionable since we found it in five alleles from the control population. The c.5601delAAC mutation in PCDH15, leading to an in frame-deletion of a threonine residue (@VARIANT$) within the intracellular domain of the protocadherin-15 CD1 isoform, also warrants a special mention. Three protocadherin-15 isoforms (CD1-3) that differ in their intracytoplasmic regions have been reported. Already two presumably pathogenic mutations (@VARIANT$ and p.T1868del) have been found in exon 34 that is specific for CD1.",3125325,USH2A;66151,protocadherin-15;23401,p.T1868del;tmVar:p|DEL|1868|T;HGVS:p.1868delT;VariantGroup:223;CorrespondingGene:65217,p.M1853L;tmVar:p|SUB|M|1853|L;HGVS:p.M1853L;VariantGroup:286;CorrespondingGene:911,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Four genes (including AGXT2, ZFHX3, SCAP, @GENE$) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and @GENE$-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,TCF4;2407,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant c.190G>A(@VARIANT$) in @GENE$ (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MEOX1;3326,TBX6;3389,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing @GENE$/TGF-beta signalling.",6161649,ENG;92,BMP;55955,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Co-transfection of HEK293 (human embryonic kidney) cells with plasmids encoding recombinant HA-TEK (hemagglutinin-tagged @GENE$) and GFP-CYP1B1 followed by co-immunoprecipitation with anti-GFP-conjugated beads demonstrated that HA-TEK and GFP-CYP1B1 are part of the same complex. As negative control, no interaction was detected between the GFP tag and HA-TEK proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ @VARIANT$ to immunoprecipitate HA-TEK E103D and HA-TEK @VARIANT$, respectively, was significantly diminished.",5953556,TEK;397,CYP1B1;68035,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Circles, female; squares, male; gray, @GENE$/TACI C104R mutation; blue @GENE$ T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of @GENE$ and @VARIANT$ (c.310T>C) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,1
"Variant in TYRO3 (c.1037T>A; @VARIANT$) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, LRP4, LRP5, @GENE$, ROR1, @GENE$, GSK3, CK1, APC, BCL9, and BCL9L) as well. No potentially pathogenic rare variant was identified. In order to identify variant(s) in other genes which might influence the expressivity of WS phenotype in our cases, exome data was filtered by using an unbiased and hypothesis-free approach. A rare missense variant (c.101T>G; @VARIANT$) in the C2orf74 gene was identified in both affected individuals.",7877624,LRP6;1747,ROR2;55831,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (@VARIANT$, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,g.27546T>A;tmVar:g|SUB|T|27546|A;HGVS:g.27546T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous @GENE$ mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"The KCNQ1-@VARIANT$ variant is currently annotated as a mutation in the Human Gene Mutation Database (HGMD) database, having been identified in other LQTS subjects. KCNH2-p.K897T was previously associated with a prolonged QT interval in several different populations and can alter the biophysical properties of mutant channels (current density, activation, inactivation, and recovery from inactivation) and exacerbate the IKr reduction caused by other KCNH2 mutations. KCNH2-p.K897T affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, KCNE1-@VARIANT$ is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia. Nevertheless, in vitro studies demonstrated that the KCNE1-p.G38S variant causes only a mild reduction of the delayed rectifier K+ currents. Therefore, G38S could be a genetic modifier, but the evidence available does not suggest it has an overt effect on the function of the @GENE$ and @GENE$ channels.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The presence of concomitant mutations, such as the TCF3 @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the @GENE$/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
   Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the GCK gene and in exon 4 (c.872 C > G; @VARIANT$) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B).,8306687,GCK;55440,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Most had C9orf72 repeat expansion combined with another mutation (e.g. @GENE$ @VARIANT$ or @GENE$ @VARIANT$; Supplementary Table 6).,5445258,VCP;5168,TARDBP;7221,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,A321V;tmVar:p|SUB|A|321|V;HGVS:p.A321V;VariantGroup:27;CorrespondingGene:23435,0
"In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in @GENE$ (@VARIANT$, p.Asp1309Asn) and a known DCM mutation in @GENE$ (c.2770G > A; @VARIANT$).",6359299,LAMA4;37604,MYH7;68044,c.3925G > A;tmVar:c|SUB|G|3925|A;HGVS:c.3925G>A;VariantGroup:1;CorrespondingGene:3910;RS#:782046057;CA#:3965094,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), @GENE$ (rs143445685), CAPN3 (@VARIANT$), and @GENE$ (@VARIANT$) genes.",6180278,RYR1;68069,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,1
"We report digenic variants in @GENE$ and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,CELSR1;7665,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"While tagged versions of EphA2 @VARIANT$ and EphA2 T511M were effectively precipitated with Fc-fusion ephrin-A1 compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down EphA2 G355R and T511M (Fig. 7a). Consistently, internalization of @GENE$ G355R and EphA2 T511M with @GENE$ induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as H723R, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum. Low temperature incubation and salicylate treatment of cultured cells, which are thought to help with protein-folding processes, rescues the membrane localization of @VARIANT$. On the other hand, mis-localization of pendrin A372V from the plasma membrane is not restored by these treatments, suggesting these mutations may affect pendrin trafficking from the Golgi to the plasma membrane but not protein-folding.",7067772,EphA2;20929,pendrin;20132,G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CAPN11;21392,UNC13B;31376,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"        A heterozygous missense variant of c.8479C > T (@VARIANT$) in the @GENE$ gene was detected, with an ExAC allele frequency of 0.000016. This variant was predicted as pathogenic by the functional prediction programs SIFT, Polyphen-2 and MutationTaster, with a GERP score of 3.79 and a CADD score of 18.07. It was reported that homozygosity for a splice site mutation in the FREM2 gene was associated with Fraser syndrome and that compound heterozygosity for a missense mutation was related to cryptophthalmos.     Three other rare heterozygous missense variants c.13364G > A (p.Arg4455His), c.3074C > T (p.Ser1025Leu), @VARIANT$ (p.Ala2980Val) in @GENE$ were identified in CS488, CS1162 and CS1210.",7149842,FREM2;18454,KMT2D;86893,p. Arg2827Cys;tmVar:p|SUB|R|2827|C;HGVS:p.R2827C;VariantGroup:13;CorrespondingGene:341640;RS#:774259178;CA#:6956146,c.8939C > T;tmVar:c|SUB|C|8939|T;HGVS:c.8939C>T;VariantGroup:27;CorrespondingGene:8085;RS#:771755912;CA#:6546765,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$).",5887939,DVL3;20928,SCRIB;44228,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"We did not find a mutation in @GENE$ in any of the individuals carrying a mutation in PROKR2 or PROK2, either. However, one of the patients heterozygous for the @VARIANT$ mutation in @GENE$ (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in KAL1 exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,FGFR1;69065,PROKR2;16368,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0
"In patient AVM028, the de novo heterozygous missense variant c.311T>C (@VARIANT$), in the functional inhibition of zinc metalloproteinases (NTR) domain, was identified in TIMP3 (table 1), which encodes a tissue metalloproteinase inhibitor. @GENE$ inhibits VEGF-mediated angiogenesis by blocking VEGF/VEGFR2 binding (figure 3), a function considered independent of metalloproteinase inhibition and unique to TIMP3 compared with other known TIMPs.  In patient AVM359, the de novo heterozygous missense variant c.1592G>A (p.Cys531Tyr) was identified in SCUBE2 (table 1), which encodes a membrane-associated multidomain protein. The variant is predicted to affect a conserved site (SIFT=0, PolyPhen2=1, GERP++=5.68, CADD=24.6). SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The @VARIANT$ (p.Cys531Tyr) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies.",6161649,TIMP3;36322,SCUBE2;36383,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"                              In the patient with the monoallelic mutation in exon 1 (@VARIANT$), additional studies were carried out to search for further genetic defects. A PCR amplicon containing @GENE$ exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (rs373270328), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (@VARIANT$;[=]) (p.Arg80Cys) in the @GENE$ gene.",5527354,GNRHR;350,PROKR2;16368,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,c.[238C > T];tmVar:c|SUB|C|238|T;HGVS:c.238C>T;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,1
"As shown in Supplementary Fig. 3a, the mutant HA-@GENE$ proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and @VARIANT$ showed perturbed interaction with HA-TEK. The residues @VARIANT$, I148, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal TEK domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary CYP1B1-binding site. To directly test this, we determined the CYP1B1-binding domain of TEK. We generated two TEK variants encoding HA-tagged N-terminal extracellular domain (amino acids 1-815; HA-TEKN) and C-terminal intracellular domain (816-1124; HA-TEKC). Co-immunoprecipitation with GFP-CYP1B1 showed that CYP1B1 associated predominantly with HA-TEKC; however, although low yet detectable HA-TEKN could also be pulled down with GFP-@GENE$ (Supplementary Fig. 3B; arrows).",5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103;tmVar:p|Allele|E|103;VariantGroup:2;CorrespondingGene:7010;RS#:572527340,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and SCN5A @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while @GENE$ mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on @GENE$ p.307_308del and SCN5A p.R1865H by WES and predisposing genes analyses.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in MYO7A and c.158-1G>A in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in @GENE$. Another variation, @VARIANT$ in intron 3 of PCDH15, was derived from the proband and his father.",3949687,PCDH15;23401,MYO7A;219,Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,DVL3;20928,FZD1;20750,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, @VARIANT$), MBD5 (NM_018328.4, c.2000T>G, @VARIANT$), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (@VARIANT$) and @GENE$: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,p.R559W;tmVar:p|SUB|R|559|W;HGVS:p.R559W;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, @GENE$, @GENE$, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,DCC;21081,PLXNA1;56426,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the @GENE$ missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a @GENE$ (@VARIANT$;p.I436V) mutation inherited from an unaffected father.",5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
MAN1B1 Protein Levels Were Decreased in Mutant Fibroblasts Expression of @GENE$ and @GENE$ was examined in lysates of fibroblasts derived from skin biopsies of unaffected family members with heterozygous mutation in only SEC23A and heterozygous mutations in both SEC23A and MAN1B1 and from affected patients (mutant fibroblasts). No significant differences were observed in the level of SEC23A in any of the samples (Fig. 3A; Supplemental Fig. S4A). Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts.,4853519,MAN1B1;5230,SEC23A;4642,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: @VARIANT$, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,TOR2A;25260,ATP2A3;69131,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0
"   Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (c.5747A>G, @VARIANT$) in CACNA1C. (B) Amino acid sequencing alignments of CANCA1C indicate that Q1916 is highly conserved across mammals (red font). (C) Topology model of the alpha-subunit of LTCC. The localization of the mutation is indicated by a red dot, and polymorphisms are indicated by green dots. (D) A variant (c.3578G>A, @VARIANT$) in SCN5A.",5426766,CACNA1C;55484,SCN5A;22738,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and @GENE$ @VARIANT$ with @GENE$ @VARIANT$ and SETX p.T14I).,4293318,TAF15;131088,SETX;41003,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,1
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and @GENE$ (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 p.P642R, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in MYO7A and c.158-1G>A in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous @VARIANT$ transition in exon 20, which results in an alanine to a serine (Ala771Ser) in @GENE$. Another variation, @VARIANT$ in intron 3 of PCDH15, was derived from the proband and his father.",3949687,PCDH15;23401,MYO7A;219,2311G>T;tmVar:c|SUB|G|2311|T;HGVS:c.2311G>T;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,KAL1;55445,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Myopathy With @GENE$ and @GENE$ Variants: Clinical and Pathological Features Objective The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Patients and methods Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (@VARIANT$, p.Pro392Leu) and a heterozygous variant in TIA1 (@VARIANT$, p.Asn357Ser).",5868303,SQSTM1;31202,TIA1;20692,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Mutations in genes involved in WNT/beta-catenin signaling, including AXIN2 WNT10A, WNT10B, LRP6, and @GENE$, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(@VARIANT$), @VARIANT$, and p.(Asn1075Ser). The three missense mutations were predicted to cause structural destabilization of the LRP6 protein. Two probands carrying both an @GENE$ mutant allele and a WNT10A variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance.",8621929,KREMEN1;12935,LRP6;1747,Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.(Ala754Pro);tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"GJB2 Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected @GENE$ Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (rs121908073), and a novel variant, p.W482R of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1). The recessive mutation @VARIANT$ was previously reported as a single founder mutation of TMC1.",4998745,GJB2;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R34X;tmVar:p|SUB|R|34|X;HGVS:p.R34X;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,KCNH2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,HS1BP3;10980,MRPL15;32210,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"On the other hand, EphA2 overexpression did not affect localization of @VARIANT$.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f).",7067772,pendrin;20132,ephrin-B2;3019,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
" Finally, a subject with the heterozygous @VARIANT$ mutation in @GENE$ (SH60-136) carried a p.D771N variant in @GENE$ (WFS1) (NM_001145853) according to TES. However, neither p.R143W in GJB2 nor @VARIANT$ in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).",4998745,GJB2;2975,Wolfram syndrome 1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,SCRIB;44228,CELSR2;1078,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,0
"Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation c.4421C > T in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"One patient had a novel de novo variant of @GENE$ (@VARIANT$, p. Ser509fs) and a hot spot variant of @GENE$ (c.533G > C, @VARIANT$) simultaneously.",8796337,KAl1;55445,PROKR2;16368,c.1524delA;tmVar:c|DEL|1524|A;HGVS:c.1524delA;VariantGroup:17;CorrespondingGene:3730,p. Trp178Ser;tmVar:p|SUB|W|178|S;HGVS:p.W178S;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917,1
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).    DISCUSSION In this study, we performed exome sequencing on 584 patients with @GENE$ and without a molecular diagnosis.",7549550,RIPPLY1;138181,CS;56073,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"On the contrary, the functionality of the @GENE$-@VARIANT$ channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/@GENE$ @VARIANT$ mutations are shown.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and TAF15 @VARIANT$ with SETX p.I2547T and @GENE$ p.T14I).,4293318,VAPB;36163,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"Prompted by the idea of an oligogenic mechanism of disease we further looked at the presence of more frequent variants (MAF <0.1%) in individuals already harboring extremely rare variants in OPTN and TBK1 and noted that case A carrying the @VARIANT$ nonsense variant in OPTN, is compound heterozygote for mutations in OPTN as it also carries the rare variant @VARIANT$ (NM_001008211.1:c.1442C>T) in OPTN (MAF=0.0116% in ESP - CADD_Phred score: 34). In order to evaluate the likelihood of @GENE$ and @GENE$ to harbor rare compound heterozygous variants or double mutations, we applied the same stringent filters that we used for our FTLD-TDP cases to our control dataset (155 Harvard PGP controls and 100 parents of intellectual disability patients).",4470809,OPTN;11085,TBK1;22742,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Ala481Val;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"In fact, skin biopsies from the proband and her sister depicted preponderance of under-carboxylated @GENE$, when examined by immunohistochemistry using specific antibodies that distinguish the fully carboxylated and under-carboxylated forms of the protein. Furthermore, assay of total ucMGP in plasma, which has been recently suggested to serve as a biomarker of cardiovascular calcification, was reduced in patients with skin findings, apparently reflecting tissue mineralization.   An intriguing observation in our family was the presence of PXE-like cutaneous features, with profound mineralization, in the proband's mother and aunt. These two individuals were heterozygous carriers of @VARIANT$ mutation in @GENE$ and @VARIANT$ in GGCX.",2900916,MGP;693,ABCC6;55559,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"We identified four genetic variants (@GENE$-p.R583H, KCNH2-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$) in an LQTS family.",5578023,KCNQ1;85014,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"M2, @GENE$: p.(E387K). M3, CYP1B1: p.(E173*). M4, PITX2: @VARIANT$. M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"(A) Patient with homozygous variants in both @GENE$ and @GENE$ genes. NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and @VARIANT$ (R284C) in ANO5 and SGCA genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in ANO5 gene and one pathogenic variant in COL6A2 gene indicating multiple gene contributions for an unusual presentation.",6292381,ANO5;100071,SGCA;9,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,1
"In our study, @VARIANT$(p. Arg631*) and c.1267C > T(p. Arg423*) were the two reported variants, while c.1525delA(p. Ser509fs) and c.1524del A(@VARIANT$) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of KAl1 gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function.         @GENE$ (PROK2) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the PROKR2 and PROKR2 genes, which can be passed down through autosomal dominant or oligogenic inheritance. In our study, 40% of patients developed PROK2/@GENE$ variants, which was significantly higher than the 9% in the Caucasian population.",8796337,Prokineticin-2;9268,PROKR2;16368,c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223,p. Ser509fs;tmVar:p|FS|S|509||;HGVS:p.S509fsX;VariantGroup:19;CorrespondingGene:3730,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"A novel missense mutation was found in @GENE$ (@VARIANT$, p.R133H). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, @VARIANT$ and p.S1067L, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001).",6098846,DUOXA2;57037,DUOX2;9689,c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341,p.H678R;tmVar:p|SUB|H|678|R;HGVS:p.H678R;VariantGroup:21;CorrespondingGene:50506;RS#:57659670;CA#:7538401,0
"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).",8152424,CDON;22996,CCDC88C;18903,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ @GENE$ proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The @GENE$ gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations.",8446458,PROKR2;16368,DUSP6;55621,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"We identified four genetic variants (@GENE$-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and @GENE$-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (@VARIANT$) in the MITF gene. Moreover, a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the C2orf74 has also been identified. The C2orf74 is an uncharacterized gene present in the linked region detected by DominantMapper. Variants in @GENE$ and C2orf74 follows autosomal dominant segregation with the phenotype, however, the variant in C2orf74 is incompletely penetrant. We proposed a digenic inheritance of variants as an underlying cause of WS2 in this family. Introduction Waardenburg syndrome (WS) is a group of rare hereditary disorders. It is characterized by pigmentary defects of hair (white forelock), eyes (heterochromia iridis) and skin (hypo-pigmented skin), abnormalities in the inner ear (bilateral sensorineural hearing impairment), and dystopia canthorum (lateral displacement of the inner canthi of the eyes). WS syndrome has been categorized into four major types (@GENE$, WS2, WS3 and WS4).",7877624,MITF;4892,WS1;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"  Recently, Gifford et al., identified three missense variants in MKL2 (@VARIANT$), @GENE$ (Leu387Phe), and @GENE$ (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MYH7;68044,NKX2-5;1482;4824,Gln670His;tmVar:p|SUB|Q|670|H;HGVS:p.Q670H;VariantGroup:2;CorrespondingGene:57496,Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and @GENE$ @VARIANT$ with SETX p.I2547T and SETX p.T14I).",4293318,VAPB;36163,TAF15;131088,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"    A new pathogenic variant in @GENE$ affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, @VARIANT$, was identified in patient #3.",6567512,BBS2;12122,BBS7;12395,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by @GENE$. 20  The identified @GENE$ (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: @VARIANT$, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,OGG1;1909,CUX1;22551,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,0
"A single @GENE$ mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB6;4936,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, @VARIANT$), LAMA2 @VARIANT$ (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization.",8739608,SCN5A;22738,KCNH2;201,c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,VAPB;36163,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"@GENE$Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in @GENE$ (DCC)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,CCDC88;49992,DCC netrin 1 receptor;21081,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"   Missense variants in the @GENE$ gene were detected in four patients: the T338I variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients.",6707335,NEFH;40755,GRN;1577,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0
"Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts.    Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in @GENE$, rs143224912 in SETDB1 and @VARIANT$ in S100A3, and one novel variant in S100A13, were identified. The ISG20L2 and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,S100A13;7523,ISG20L2;12814,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and TAF15 @VARIANT$ with @GENE$ p.I2547T and SETX p.T14I).,4293318,VAPB;36163,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"    Sanger sequencing Sanger sequencing was performed on available samples for confirmation of GFI1 and @GENE$ variants in family members to perform segregation analysis. Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in @GENE$ (@VARIANT$/c.1145A > G) and MYO6 (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,MYO6;56417,GFI1;3854,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"Mutations of @GENE$ and @GENE$ genes are closely related to LQTS. The mutations of KCNH2 @VARIANT$ and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous SCN5A @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Four genes (including @GENE$, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,AGXT2;12887,SCAP;8160,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"This mutation changes codon 554 from arginine to a stop codon (c.1160C>T; @VARIANT$) and has been previously reported. The mother did not carry this luteinizing hormone/choriogonadotropin receptor (@GENE$) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the @GENE$, SRY, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant @VARIANT$ lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant.",5893726,LHCGR;37276,AMH;68060,p.Arg554Stop;tmVar:p|SUB|R|554|X;HGVS:p.R554X;VariantGroup:1;CorrespondingGene:3973;RS#:368991748,Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,0
"Gln91Arg, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant @VARIANT$ of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. CDON seems to act similarly as @GENE$ through a digenic/oligogenic model to contribute to IHH. Case P06 had a missense variant in GADL1 (p. Ser221Cys), predicted as probably damaging. GADL1 expression is present during early brain development and is higher in olfactory bulb than that in other tissues, where is an active area for regeneration and migration of GnRH neurons. Consistent with this observation, case P06 was affected by anosmia, indicating that the function of GADL1 might be involved in the etiology of IHH (Table 2). A de novo @GENE$ frameshift deletion (p. Gly52Asnfs*14) resulting in truncation of the protein was detected in case P09.",8152424,CCDC88C;18903,SPRED3;28061,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
"(A) Patient with homozygous variants in both @GENE$ and SGCA genes. NGS reads indicated the identification of homozygous missense pathogenic variants @VARIANT$ (p.R758C) and @VARIANT$ (R284C) in ANO5 and @GENE$ genes, respectively.",6292381,ANO5;100071,SGCA;9,c.2272C>T;tmVar:c|SUB|C|2272|T;HGVS:c.2272C>T;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, @VARIANT$ in @GENE$, @VARIANT$ in @GENE$ and rs138355706 in S100A3, and one novel variant in S100A13, were identified.",6637284,ISG20L2;12814,SETDB1;32157,rs3795737;tmVar:rs3795737;VariantGroup:5;CorrespondingGene:81875;RS#:3795737,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,0
"The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and @GENE$ @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,SCRIB;44228,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,1
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,CAPN11;21392,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"   Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (c.5747A>G, @VARIANT$) in CACNA1C. (B) Amino acid sequencing alignments of CANCA1C indicate that Q1916 is highly conserved across mammals (red font). (C) Topology model of the alpha-subunit of LTCC. The localization of the mutation is indicated by a red dot, and polymorphisms are indicated by green dots. (D) A variant (@VARIANT$, p.R1193Q) in SCN5A.",5426766,CACNA1C;55484,SCN5A;22738,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,c.3578G>A;tmVar:c|SUB|G|3578|A;HGVS:c.3578G>A;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"The @VARIANT$ (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"Her fasting C-peptide was 0.86 ng/mL (reference range: 0.5-3 ng/dL) and 60-minute stimulated C-peptide was 1.96 ng/mL. Due to the negative diabetes autoantibody panel, she underwent genetic testing as part of the SEARCH monogenic diabetes ancillary study at 11 years of age demonstrating a heterozygous missense mutation in exon 4 of @GENE$, @VARIANT$ (c.379C>T) and a heterozygous frameshift mutation in exon 4 of HNF1A, P291fsinsC (@VARIANT$). @GENE$ therapy was completely discontinued and she was started on glipizide (1.25 mg once daily) with the dose titrated to 2.5 mg once daily based on blood sugar checks, with weekly blood sugar reviews and close support from a diabetes specialist nurse practitioner.",4090307,HNF4A;395,Insulin;173,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,0
"Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,1
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and @VARIANT$; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of NOD2 protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the @VARIANT$ substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,R351G;tmVar:p|SUB|R|351|G;HGVS:p.R351G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In our studied family, SH107-225 with profound SNHL carried @VARIANT$ in @GENE$ and a de novo variant, @VARIANT$ in @GENE$. DFNB1 as a molecular etiology was excluded from this subject, while digenic inheritance of SNHL can be proposed for this subject because the pathogenic potential of p.R341C was strongly supported by significant conservation of the p.R341 residue among various species and by the absence of this variant among the 666 control chromosomes from normal hearing control subjects.",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).",8152424,DCC;21081,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, @GENE$ p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The WT structure of @GENE$ is shown in purple, and the mutant structure of FLNB is shown in green. The side chains of R/@VARIANT$ and A/T2282 are shown as sticks, and the other residues are shown as lines. (D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.R566L, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$, p.R50C).",7279190,FLNB;37480,TTC26;11786,L566;tmVar:p|Allele|L|566;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,TOR2A;25260,HS1BP3;10980,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD6;2617,FZD1;20750,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,VPS13C;41188,UNC13B;31376,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: @VARIANT$, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,UNC13B;31376,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"          Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by @GENE$/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated @GENE$. Immunocomplex of myc-pendrin @VARIANT$, S166N and @VARIANT$ was not affected.",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Notably, the common variants @GENE$-p.K897T and @GENE$-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNE1;3753,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,MAP4K4;7442,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"The @VARIANT$ and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,0
"There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0
"The c.1592G>A (@VARIANT$) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant @VARIANT$ (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant c.2075A>G (p.Asn692Ser) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, @GENE$ mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).",6161649,SCUBE2;36383,N-cadherin;20424,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The presence of concomitant mutations, such as the @GENE$ T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of @GENE$/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0
"The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .   In vitro evaluation of a similarly truncated @GENE$ isoenzyme comprising amino acids 1 to 593 alone abolished H2O2-generating activity. Moreover, similar truncations in the highly homologous @GENE$ [p.Q686*, p.R701*, p.(G418fsX482);(IVS19-2A>C), @VARIANT$] are associated with CH or severely impaired H2O2-generating activity in vitro.",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p.S965fsX994;tmVar:p|FS|S|965||994;HGVS:p.S965fsX994;VariantGroup:16;CorrespondingGene:50506,0
"A novel variant SCRIB c.1853A > G (@VARIANT$) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 @VARIANT$ and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,CELSR1;7665,SCRIB;44228,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (@VARIANT$) and @GENE$: c.1229C>A (@VARIANT$), @GENE$: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"  Discussion Here, we presented a rare large Chinese family with ER-associated SCD, in which the disease phenotypes were mainly caused by a @GENE$-@VARIANT$ mutation and modulated by the @GENE$-@VARIANT$ variant and sex (Fig 7).",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,SCRIB;44228,CELSR2;1078,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation c.4421C > T in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,CDH23;11142,USH1G;56113,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of @GENE$) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The @VARIANT$ (p.Cys531Tyr) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant @VARIANT$ (p.Arg565Gln) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant c.2075A>G (p.Asn692Ser) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, @GENE$ mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).",6161649,MAP4K4;7442,N-cadherin;20424,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CAPN11;21392,SPTBN4;11879,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Four potential pathogenic variants, including @GENE$ @VARIANT$ (NM_001160160, c.G5594A), LAMA2 @VARIANT$ (NM_000426, c.G2881A), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Data were fit with a Boltzmann distribution {I = Imax/(1 + exp[(V1/2 - V)/k])} for KCNQ1-WT+@GENE$ (solid line) and for KCNQ1-@VARIANT$+KCNE1 (dashed line); (E) Time constants of the tail current from CHO-K1 cells transiently transfected with @GENE$-WT+KCNE1 (solid line, n = 7) or KCNQ1-p.R583H+KCNE1 (open circles, n = 8) plotted as a function of the activation step voltage. The decay of the potassium current recorded during the test pulse to -30 mV was fit with a single exponential function (area delimited by dotted lines shown in F); (F) Stimulation protocol. Data are shown as mean +- SEM.             Functional properties of the KCNH2-@VARIANT$ variant.",5578023,KCNE1;100760439,KCNQ1;100761481,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"Moller et al. reported an index case with digenic variants in MYH7 (L1038P) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (@VARIANT$) and @GENE$ (Asn83His), both sarcomeric genes.",6359299,MYBPC3;215,TNNT2;68050,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type @GENE$ and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. The residues @VARIANT$, I148, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal @GENE$ domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary CYP1B1-binding site.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103;tmVar:p|Allele|E|103;VariantGroup:2;CorrespondingGene:7010;RS#:572527340,0
"Specifically, the mother and her twin sister were heterozygous for the GGCX missense mutation @VARIANT$ and the ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings. However, the proband's younger brother and father were heterozygous carriers of the p.S300F mutation in the @GENE$ gene while they also carried the p.R1141X mutation in the ABCC6 gene; they did not display any signs of cutaneous findings or hematologic disorder.       Assay of gamma-glutamyl carboxylase activity Previous studies have clearly demonstrated that the p.R1141X mutation in the @GENE$ gene in heterozygous carriers does not cause PXE.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in  Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, @GENE$, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for EVC, FGF10, GLI2, RIPK4 and @GENE$; and RET for PIK3R3 with PTPN11, which also is connected with RIPK4.",6726737,GLI2/3;2736;2737,EYA1;74943,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Given their offspring was mutation carriers, we might infer that II-4 and III-1 also harbored the @GENE$-Q1916R mutation. Notably, not all CACNA1C-@VARIANT$ carriers (II-3, II-6, III-4, III-5, III-7, IV-1, IV-3, IV-4 and obligate carriers II-4 and III-1) manifested the positive phenotypes (ER pattern in ECG or nocturnal SCD). This phenotypic incomplete penetrance might be modified by @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Therefore, in this study, @GENE$ @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of @GENE$ p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 @VARIANT$ and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"(D) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.637G>A were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis. (E) The EDA mutation c.466C>T and @GENE$ mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.",3842385,WNT10A;22525,EDA;1896,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"25  The RYR3 (NM_001036: c.7812C > G, @VARIANT$) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the @GENE$ (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, @GENE$ variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis.",7689793,CAPN9;38208,TRIP6;37757,p.Asn2604Lys;tmVar:p|SUB|N|2604|K;HGVS:p.N2604K;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the @GENE$ [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; @VARIANT$] variants which displayed digenic inheritance (Fig. 1a).,6053831,PCDH15;23401,USH1G;56113,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,p.(Asp365Asn);tmVar:p|SUB|D|365|N;HGVS:p.D365N;VariantGroup:1;CorrespondingGene:124590;RS#:538983393;CA#:8753931,1
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,MYOD1;7857,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"Among the 8 novel variants, 4 were classified as P (@VARIANT$ and @VARIANT$ in @GENE$, p.T803fs in DUOX2) or LP (p.D137E in @GENE$), the other were classified as VUS.",7248516,TSHR;315,DUOX2;9689,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,p.K618*;tmVar:p|SUB|K|618|*;HGVS:p.K618*;VariantGroup:4;CorrespondingGene:7253,0
"  Recently, Gifford et al., identified three missense variants in @GENE$ (@VARIANT$), @GENE$ (Leu387Phe), and NKX2-5 (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MKL2;40917,MYH7;68044,Gln670His;tmVar:p|SUB|Q|670|H;HGVS:p.Q670H;VariantGroup:2;CorrespondingGene:57496,Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,DVL3;20928,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,0
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for @GENE$ (Cx26) and connexin 31 (@GENE$) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,connexin 26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"We identified four genetic variants (@GENE$-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-@VARIANT$ and @GENE$-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(Cys331Thr) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly). Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(Ser872Gly) variant in PKD1, while only one fetus inherited the p.(@VARIANT$) PKD2 variant.",7224062,PKD1;250,PKD2;20104,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"@GENE$:@VARIANT$, predicted to alter the splice donor site of intron 3, has been classified as pathogenic. @GENE$:@VARIANT$ is a non-truncating mutation, but was previously reported as disease-causing.",3949687,PCDH15;23401,MYO7A;219,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,0
"Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, @GENE$ c.28C > A (@VARIANT$) and @GENE$ @VARIANT$ (p.Arg248Cys).",7463850,GRIN2A;645,PLXNB2;66630,p.Leu10Met;tmVar:p|SUB|L|10|M;HGVS:p.L10M;VariantGroup:0;CorrespondingGene:2903,c.742C > T;tmVar:c|SUB|C|742|T;HGVS:c.742C>T;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Similarly, SH170-377 carrying the @VARIANT$ mutation in @GENE$ also contained a previously reported homozygous @VARIANT$*36 mutant allele in Myosin XVA (MYO15A) (NM_016239) (Table 1).       Although no other causative deafness mutation was detected in the initial analysis of TES data, Sanger sequencing for the low coverage area (<10x) in TES (see Table S2, Supplemental Content, which illustrates regions showing significantly low depth of coverage in TES: OTOF, STRC, and OTOA) revealed the two known pathogenic STRC mutations as a compound heterozygous configuration in SB175-334 (Table 1). To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, DFNB3, and DFNB16, respectively.  Finally, a subject with the heterozygous p.R143W mutation in GJB2 (SH60-136) carried a p.D771N variant in @GENE$ (WFS1) (NM_001145853) according to TES.",4998745,GJB2;2975,Wolfram syndrome 1;4380,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.Glu396Argfs;tmVar:p|FS|E|396|R|;HGVS:p.E396RfsX;VariantGroup:15;CorrespondingGene:51168;RS#:772536599;CA#:8423043,0
"  Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in SQSTM1 (p.Pro392Leu) and a variant in TIA1 (@VARIANT$). At the time of this report, only a single prior myopathy case with the same genetic variants has been reported, but the clinical and myopathological features were not illustrated. There are also two further cases of MRV having the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), one of whom was previously reported as having a SQSTM1-MRV. Although the causality of the coexisting @GENE$ and @GENE$ variants in myopathy has not been proven, our affected individuals from three unrelated family provide further support to the digenic nature of this myopathy.",5868303,SQSTM1;31202,TIA1;20692,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"On the other hand, mutant GFP-@GENE$ A115P and @VARIANT$ showed perturbed interaction with HA-@GENE$. The residues E103, I148, and @VARIANT$ lie in the N-terminal extracellular domain of TEK (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,Q214;tmVar:p|Allele|Q|214;VariantGroup:10;CorrespondingGene:7010,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, @GENE$ p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, @VARIANT$ was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,SCRIB;44228,CELSR1;7665,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0
"Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"In addition, the c.580G > T (@VARIANT$) and @VARIANT$ (p. Gly716Val) variants were identified by the software as harmful. In previous studies, the phenotype of the FGFR1 gene was not completely dominant, and most of the variants were inherited from a normal father or mother. However, most of the patients in our study had de novo variants; one patient inherited the variants from his father, while the other patient inherited the variants from her mother. Two female patients had a frameshift variant of the FGFR1 gene, which showed an infantile uterus and ovary. In the group with a nonreproductive phenotype, variants in the FGFR1 gene were found in one patient with cleft lip and palate, which was consistent with the report of a previous study. Another patient presented with a renal cyst and short stature. Therefore, anosmia, sexual dysplasia, irregular tooth alignment, cleft lip and palate, syndactyly, and renal abnormalities were common phenotypes of IHH patients with @GENE$ gene variants.                               The @GENE$ gene is located on chromosome 8q12.1 and is autosomal dominant, encoding chromosomal helicase DNA-binding protein 7.",8796337,FGFR1;69065,CHD7;19067,p. Gly194Cys;tmVar:p|SUB|G|194|C;HGVS:p.G194C;VariantGroup:8;CorrespondingGene:3730;RS#:1064796777,c.2147G > T;tmVar:c|SUB|G|2147|T;HGVS:c.2147G>T;VariantGroup:2;CorrespondingGene:2260,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, @GENE$ = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 6;4936,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"      WES revealed heterozygous mutations in two genes known to affect hypothalamic and pituitary development: @VARIANT$;p.R85C in @GENE$ (MIM 607123; NM_144773.2; rs141090506) inherited from an unaffected mother and @VARIANT$;p.I436V in @GENE$ (MIM 606417; NM_018117.11; rs34602786) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1).",5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,TRPV4;11003,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. Allele frequency for @VARIANT$ within the population was calculated from exome sequencing of 2000 individuals and was found to be 0.1% (unpublished data from the Saudi Human Genome Project; www.saudigenomeprogram.org).",6637284,S100A3;2223,S100A13;7523,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, p.Arg896Trp) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"@GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2).",6161649,SCUBE2;36383,VEGFR2;55639,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,VPS13C;41188,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, @GENE$, @GENE$, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,ANOS1;55445,DCC;21081,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Functional impact of the rare variants The two missense @GENE$ variants (@VARIANT$ and (p.(C498R)) and one of the PITX2 amino acid substitutions (p.(P179T)) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation. The functional impact of the second @GENE$ amino acid substitution, p.(A188T), could not be functionally evaluated due to DNA cloning difficulties. In fact, the two FOXC2 amino acid changes were found to be hypomorphic whereas the PITX2 amino acid substitution (@VARIANT$) behaved experimentally as a hypermorphic variant.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"The DNA sequencing chromatograms from the proband show two LRP6 and one @GENE$ heterozygous mutations. While both @GENE$ variants, p.(Ser127Thr) and p.(@VARIANT$), were inherited from her father, the WNT10A mutation, @VARIANT$ was maternally derived.",8621929,WNT10A;22525,LRP6;1747,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, @VARIANT$, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,c.379T>A;tmVar:c|SUB|T|379|A;HGVS:c.379T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (@VARIANT$; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different @GENE$ mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,TIA1;20692,SQSTM1;31202,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ @VARIANT$ and @GENE$ @VARIANT$), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD6;2617,CELSR2;1078,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,1
"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in MYD88 gene and a homozygous splice-donor mutation (@VARIANT$) in CARD9 gene. (D) Western Blot of @GENE$ and @GENE$ proteins performed on PBMC, EBVB, and PHA derived T cell lines.",6383679,CARD9;14150,MYD88;1849,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,UNC13B;31376,SPTBN4;11879,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Interestingly, four of these @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Consistently, internalization of EphA2 @VARIANT$ and EphA2 T511M with pendrin induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of @GENE$ did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as H723R, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum. Low temperature incubation and salicylate treatment of cultured cells, which are thought to help with protein-folding processes, rescues the membrane localization of H723R. On the other hand, mis-localization of @GENE$ A372V from the plasma membrane is not restored by these treatments, suggesting these mutations may affect pendrin trafficking from the Golgi to the plasma membrane but not protein-folding. Here, we found that pendrin A372V, @VARIANT$, Q446R, and G672E did not bind to EphA2.",7067772,EphA2;20929,pendrin;20132,G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,0
"Only three variants were homozygous in three patients: (1) @GENE$: c.2779A>G (p.M927V) in one patient, (2) DUOX2:c.3329G>A (@VARIANT$) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$).",5887939,DVL3;20928,SCRIB;44228,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,PDGFRB;1960,SLC20A2;68531,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"Pathogenic effects of GBE1 @VARIANT$ and NDUFS8 I126V variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the @GENE$ p.T4823 M variant in MH. Subject R462 was diagnosed as MHS, which appeared to correlate with CACNA1S @VARIANT$, previously reported in a single MHS subject. However, the frequency of this variant in the general population is about 20-fold higher than the frequencies of pathogenic CACNA1S variants associated with MHS. It is also important to note that the diagnostic test for MH has a high false-positive rate of 22%, which raises the possibility that MHS diagnosis in subject R462 may be false. Based on these results, we also ruled out a pathogenic role of the @GENE$ p. R498L variant in MH.",6072915,RYR1;68069,CACNA1S;37257,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (@VARIANT$), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of TEK to respond to ligand stimulation, indicating perturbed @GENE$ signaling.",5953556,CYP1B1;68035,TEK;397,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"One heterozygous @GENE$ splice mutation (@VARIANT$) has been described. However, the only KS individual within the family also had a heterozygous @GENE$ mutation (@VARIANT$), suggesting digenic disease.",3888818,NELF;10648,FGFR1;69065,c.1159-14_22del;tmVar:c|DEL|1159-14_22|;HGVS:c.1159-14_22del;VariantGroup:12;CorrespondingGene:26012,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,1
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis.         We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: 179260153C/T, refSNP ID rs4935; Chr5: 179260213G/A, @VARIANT$; Chr5: 179264731T/C, rs10277; Ch5: 179264915G/T, rs1065154 ].",5868303,TIA1;20692,SQSTM1;31202,c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,rs4797;tmVar:rs4797;VariantGroup:0;CorrespondingGene:8878;RS#:4797,0
"Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) GBE1 R524Ter; 2) PCCB G407RfrTer14; 3) NUBPL IVS8DC; 4) @GENE$ Y299Ter. Two additional variants, @VARIANT$ in @GENE$ and @VARIANT$ in CACNA1S, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,OAT;231,RYR1;68069,p. T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0
"This analysis indicated that the @GENE$ variant c.1663G>A (rs138172448), which results in a @VARIANT$ change, and the @GENE$ gene variant c.656C>T (@VARIANT$), which results in a p.Thr219Ile change, are both predicted to be damaging.",6180278,CAPN3;52,DES;56469,p.Val555Ile;tmVar:p|SUB|V|555|I;HGVS:p.V555I;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"We observed that isoproterenol could enhance the activity of LTCC in the HEK293T cells, which may be associated with the evocation of @GENE$/protein kinase A pathways by the activation of the endogenous beta2 adrenoreceptors. In summary, we investigated an extremely rare large ERS family with a high incidence of nocturnal SCD, in which we found a pathogenic mutation in @GENE$ (@VARIANT$) with loss-of-function. The penetrance was also incomplete, which was modified by a gain-of-functional SCN5A-@VARIANT$ variant and sex.",5426766,cAMP;110678,CACNA1C;55484,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD6;2617,FAT4;14377,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,0
"These facts suggest an essential role of these amino acids on @GENE$ function that might be conserved throughout evolution. To examine whether these mutations affect the ligand-binding specificity of EphA2 to ephrin-A and ephrin-B, a pull down assay was performed with HEK293T cells due to their low level of endogenous EphA2 expression (Supplementary Fig 7a, b). While tagged versions of EphA2 G355R and EphA2 @VARIANT$ were effectively precipitated with Fc-fusion ephrin-A1 compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down EphA2 G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 G355R and EphA2 T511M with pendrin induced by @GENE$ but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as @VARIANT$, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum.",7067772,Eph;20936,ephrin-B2;3019,T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"A complete loss of this trans-activational activity was noted for the proteins with missense mutations located in the LBD (p.His310Asp and p.Asp364Tyr), the SF1 @VARIANT$, as well as both frame-shift mutations assayed (p.Arg89Glyfs*17 and p.Leu209Cysfs*87) (Figure 3). Intriguingly, a nonsense SF1 variant (p.[@VARIANT$;Tyr211*]) seemed to retain a low level of activity (Figure 3). A similar pattern was seen with the SRY/@GENE$ transfected cells; however, the magnitude of activation was in general lower than that of the SOX9/SF1 transfection (Figure 3). All the SF1 variants identified in our DSD patients showed reduced transactivation activity in vitro when co-transfected with SRY or @GENE$. This suggests that the reason these variants are pathogenic is because they result in a dramatic reduction or loss of SF1 transactivation activity in these patients.",5765430,SF1;138518,SOX9;294,p.47_54del;tmVar:p|DEL|47_54|;HGVS:p.47_54del;VariantGroup:30;CorrespondingGene:2516,Pro210Gln;tmVar:p|SUB|P|210|Q;HGVS:p.P210Q;VariantGroup:5;CorrespondingGene:2626;RS#:575307727;CA#:4630899,0
"Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, GRIN2A @VARIANT$ (p.Leu10Met) and @GENE$ c.742C > T (@VARIANT$). The variant in @GENE$ was novel and was predicted to be damaging using both SIFT and PolyPhen.",7463850,PLXNB2;66630,GRIN2A;645,c.28C > A;tmVar:c|SUB|C|28|A;HGVS:c.28C>A;VariantGroup:0;CorrespondingGene:2903,p.Arg248Cys;tmVar:p|SUB|R|248|C;HGVS:p.R248C;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0
"It has been reported that @GENE$ localises to the basal body and the proximal regions of the cilium, a non-motile microtubule-based organelle that projects from the cell surface. Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between FLNB and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ @GENE$ proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).",7279190,FLNB;37480,TTC26;11786,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, @VARIANT$, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,c.2450C>G;tmVar:c|SUB|C|2450|G;HGVS:c.2450C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/@GENE$ @VARIANT$ mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, @VARIANT$), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of @GENE$ and SCN5A genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,LAMA2;37306,KCNH2;201,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 3;7338,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Similarly, our results indicate that increased transactivation associated with the @VARIANT$ PITX2 mutation is not related with altered protein stability, protein conformation or subcellular localization. Proline possesses a hydrophobic side chain, whereas threonine side chain has both hydrophilic and hydrophobic functions. Therefore, this amino acid replacement may affect protein interactions taking place in the transcriptional inhibitory domain where it is located, leading to increased @GENE$ activity. In this line, an increased side chain polarity associated with amino acid substitution p.(A188T) could also interfere protein interactions involving the first PITX2 transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, @GENE$ variants p.S36S (synonymous) and @VARIANT$ (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and FOXC2-AS1 genes.",6338360,PITX2;55454,FOXC2;21091,p.P179T;tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,c.*38T>G;tmVar:c|SUB|T|*38|G;HGVS:c.*38T>G;VariantGroup:6;CorrespondingGene:103752587;RS#:199552394,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB3;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the @VARIANT$ (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of @GENE$ and @GENE$ in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against Cx26 (a) and Cx31 (b).,2737700,Cx31;7338,Cx26;2975,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,497A>G;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (@VARIANT$) in the @GENE$ gene. Moreover, a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the @GENE$ has also been identified.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,TYRO3;4585,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (@VARIANT$, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,g.68531T>G;tmVar:g|SUB|T|68531|G;HGVS:g.68531T>G;VariantGroup:11;CorrespondingGene:4040,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (@GENE$ @VARIANT$).",8152424,FGFR1;69065,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"    Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and @GENE$-@VARIANT$, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and @GENE$-@VARIANT$ were previously reported to produce more severe phenotypes when combined with disease-causing alleles.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (c.229C>T; @VARIANT$) and d) the c.238-241delATTG (@VARIANT$) in @GENE$. Mutation name is based on the full-length @GENE$ (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A13;7523,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"@GENE$ gene might interact with MITF gene product and give rise to the spectrum of phenotype varying from severe phenotype with complete penetrance to partial features. Conclusion In this study, we analysed a large family segregating Waardenburg syndrome type 2 to identify the underlying genetic defects. Whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach was performed and a novel single nucleotide deletion mutation (@VARIANT$) in the @GENE$ gene and a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the C2orf74 was identified.",7877624,C2orf74;49849,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,DFNB1;2975,gap junction protein beta 3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Furthermore, these missense mutations were either unreported in the ExAC population database (@VARIANT$, and p.Tyr283His) or reported at rare frequencies (p.Gln106Arg, at 0.2%; p.Val134Gly, at 0.0008%; p.Arg262Gln at 0.2%; and PROKR2 @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (@GENE$/@GENE$) heterozygous mutation.",5527354,GNRHR;350,PROKR2;16368,p.Arg139Cys;tmVar:p|SUB|R|139|C;HGVS:p.R139C;VariantGroup:2;CorrespondingGene:2798;RS#:1325732095,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of @VARIANT$ in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/MITF and @GENE$/GJB3 (group II). (A) In addition to c.235delC in GJB2, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,gap junction protein beta 3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"The c.1592G>A (@VARIANT$) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3).",6161649,SCUBE2;36383,MAP4K4;7442,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"17  Although the functional evidence of combined defects in oxidative DNA damage repair genes is still lacking, the coinheritance of @GENE$ and @GENE$ variants in at least three, but likely five cancer cases within one family warrants further mechanistic and clinical studies. The absence of cancer and numerous polyps in nondigenic carriers further substantiates this association. Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of MSH6 @VARIANT$ protein. In addition, the genetic marker for MAP-tumors (KRAS @VARIANT$) was absent in this tumor, which points toward retained MUTYH repair activity.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.34G > T;tmVar:c|SUB|G|34|T;HGVS:c.34G>T;VariantGroup:12;CorrespondingGene:3845;RS#:587782084;CA#:13137,0
"To further analyze the role of @GENE$ in Pendred syndrome, direct sequencing of the EPHA2 gene in 40 Japanese hearing loss patients with EVA carrying mono-allelic mutation of @GENE$ were examined. While mutation of ~70 genes causing hearing loss were previously identified as a human nonsyndromic deafness gene, they were not identified in these patients. On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,EphA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The ADD3 @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. All constructs were verified by sequencing. @GENE$ or @GENE$ depleted podocytes were transduced with WT or mutant ADD3 or KAT2B lentiviral particles, respectively.",5973622,ADD3;40893,KAT2B;20834,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0
"The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (c.[238C > T];[=]) (@VARIANT$) in the @GENE$ gene.         The @GENE$ frameshift mutation was identified in two different families and has not been reported before. It consists of an 11 base-pair deletion (@VARIANT$), and if translated, would be expected to result in a truncated protein due to a premature termination codon (p.Phe313Metfs*3).",5527354,PROKR2;16368,GNRHR;350,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,c.937_947delTTTTTAAACCC;tmVar:c|DEL|937_947|TTTTTAAACCC;HGVS:c.937_947delTTTTTAAACCC;VariantGroup:7;CorrespondingGene:2798,0
"The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes.     ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The p.Ala349Thr (c.1045G>A) mutation in exon 9 of EDA and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of WNT10A were detected.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The @VARIANT$ variant is predicted to be deleterious by four prediction programs and is absent in 13,006 control chromosomes from the National Heart, Lung, and Blood Institute's Exome Sequencing Project (ESP) and in 672 chromosomes from Middle Eastern persons (including 36 chromosomes from Palestinian persons). OTUD4 encodes a deubiquitinase (Fig. S1 in the Supplementary Appendix). The @VARIANT$ variant is predicted to be deleterious by three of four prediction programs and is found in 2 of the 13,006 chromosomes from the ESP and in none of the 672 chromosomes from Middle Eastern persons.           Both @GENE$ and @GENE$ were sequenced in nine affected persons from seven unrelated families.",3738065,OTUD4;35370,RNF216;19442,R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853,G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858,0
"Only three variants were homozygous in three patients: (1) @GENE$: c.2779A>G (p.M927V) in one patient, (2) DUOX2:@VARIANT$ (p.R1110Q) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,c.3329G>A;tmVar:c|SUB|G|3329|A;HGVS:c.3329G>A;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in @GENE$ (@VARIANT$, p.Pro392Leu) and a heterozygous variant in @GENE$ (c.1070A>G, @VARIANT$).",5868303,SQSTM1;31202,TIA1;20692,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,FGFR1;69065,DCC;21081,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and @GENE$ has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).",7549550,RIPPLY1;138181,MYOD1;7857,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"(B) The predicted 2D structure of human @GENE$ protein. The @VARIANT$ and G213 residues are in yellow. The 3D structure of @GENE$ is shown in Figure 4. The G257 residue is located at the interface of two trimers. When @VARIANT$ mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA.",3842385,WNT10A;22525,EDA;1896,R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555,G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
   Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the @GENE$ gene and in exon 4 (c.872 C > G; @VARIANT$) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the GCK variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B).,8306687,GCK;55440,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"Case A was a compound heterozygote for mutations in @GENE$, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in @GENE$. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain.",4470809,OPTN;11085,TBK1;22742,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in @GENE$ were linked to midline brain malformation. Of note, the same variant @VARIANT$ was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)p. Gln91Arg, and @GENE$ @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,CCDC88C;18903,FGFR1;69065,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,1
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Compared to the Nav1.5 protein properties of wild-type @GENE$, SCN5A p.R1865H slightly increased its molecular weight and aliphatic index but reduced its instability index. Theoretical pI, aliphatic index, and GRAVY were not affected by SCN5A p.R1865H.     Amino acids physical and chemical parameter prediction Physical and chemical parameters KCNH2-wild type KCNH2-@VARIANT$ SCN5A-wild type SCN5A-@VARIANT$   Molecular weight 14430.15 14359.07 18856.35 18872.39   Theoretical pI 9.30 9.30 12.10 12.10   Instability index 30.43 30.59 95.32 91.73   Aliphatic index 106.54 106.59 45.00 47.22   GRAVY 0.336 0.325 -0.541 -0.511                Abbreviation: GRAVY, Grand average of hydropathicity. Next, hydrophobicity analyses for wild-type and mutant proteins were performed (Table 4, Figure 5). The changed site (position 307) of @GENE$ p.307_308del was located close to the largest hydrophobic region of the protein (Figure 5a).",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys).",8152424,DCC;21081,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"Four potential pathogenic variants, including @GENE$ @VARIANT$ (NM_001160160, c.G5594A), @GENE$ @VARIANT$ (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,SCN5A;22738,LAMA2;37306,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0
"We also identified a monoallelic change in @GENE$ (c.G680A, p.Arg227Gln, @VARIANT$:G>A) in Patient 11, who also harbored a @VARIANT$ of @GENE$ (Table 3).",5765430,SRD5A2;37292,NR5A1;3638,rs9332964;tmVar:rs9332964;VariantGroup:0;CorrespondingGene:6716;RS#:9332964,single codon deletion at position 372;tmVar:|Allele|SINGLECODON|CODON372;VariantGroup:21;CorrespondingGene:2516,1
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), @GENE$: @VARIANT$ (p.G355R) and @GENE$: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,VAPB;36163,FUS;2521,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in @GENE$ (DCAF17), were inherited from unaffected father, while @GENE$ p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DMXL2;41022,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein. However, the two rare FUS variants (@VARIANT$ and P106L) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein.",6707335,SPG11;41614,ubiquilin-2;81830,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,Y25C;tmVar:p|SUB|Y|25|C;HGVS:p.Y25C;VariantGroup:12;CorrespondingGene:2521;RS#:141516414;CA#:8023442,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,GJB6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and @GENE$.       3.5. Predicted Structural Alterations and Pathogenicity of LRP6 Missense Mutations Computational prediction of the structural impact for the five LRP6 missense mutations on protein stability demonstrated that p.Met168Arg, p.Ala754Pro, and @VARIANT$ were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively. Particularly, p.Met168Arg and @VARIANT$ were highly destabilizing, as their DeltaDeltaGs were higher than 1.00 kcal mol-1.",8621929,LRP6;1747,WNT10A;22525,p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively.",8152424,PROKR2;16368,CDON;22996,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
"Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, @GENE$-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"In silico analyses (figure 3C) indicated that the @VARIANT$ residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between p.R2003H @GENE$ and @VARIANT$ @GENE$ (figure 3D).",7279190,FLNB;37480,OFD1;2677,R2003;tmVar:R2003;VariantGroup:29;CorrespondingGene:2317,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The mother and the father were asymptomatic carriers of PKHD1: c.4437_4440delCATA (p.F1479Lfs*20) and @GENE$: c.5935G > A (p.G1979R), respectively (Figure 3).      The foetuses in Family 24 and Family 25 appeared to have additional symptoms besides PKD. The couple from Family 24 had undergone abortion three times due to phenotypes similar to those in renal cystic disorders, bladder dysplasia and oligohydramnios. The sample of the third pregnancy was subjected to genetic testing using WES plus Sanger sequencing. The compound heterozygous variants of TMEM67: @VARIANT$ (@VARIANT$) and TMEM67: c.579delA (p.G195Dfs*27) were identified and likely agreed with the Meckel Gruber syndrome type 3 (@GENE$, MIM #607316), which segregated from the asymptomatic parents (Figure 3).",8256360,PKHD1;16336,MKS3;71886,c.637C > T;tmVar:c|SUB|C|637|T;HGVS:c.637C>T;VariantGroup:3;CorrespondingGene:5314;RS#:866575098;CA#:138924774,p.R213C;tmVar:p|SUB|R|213|C;HGVS:p.R213C;VariantGroup:3;CorrespondingGene:91147;RS#:866575098,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Molecular genetic studies A previously described homozygous @GENE$ nonsense mutation (c.1300C>T, @VARIANT$) had initially been identified in P1 and P2, for which their parents and unaffected sibling were heterozygous (Fig. 1). DNA was not available from the deceased sibling. The severity of the CH prompted investigation for an additional genetic mutation using whole-exome sequencing in P1 and P2. In addition to coding regions, significant intronic sequences were covered using this technique, enabling detection of a homozygous essential splice site change in @GENE$ (@VARIANT$), at the intron 14/exon 15 boundary, validated by Sanger sequencing in both cases.",5587079,DUOX2;9689,DUOX1;68136,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,1
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"This phenotypic incomplete penetrance might be modified by SCN5A-@VARIANT$ variant and sex. As shown in Table 3, all male individuals carrying the CACNA1C-Q1916R mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant @GENE$-R1193Q showed the ERS phenotypes. The female CACNA1C-Q1916R mutation carriers with SCN5A-R1193Q variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the @GENE$-@VARIANT$ mutation (IV-4) showed the ER ECG pattern.",5426766,SCN5A;22738,CACNA1C;55484,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"                    By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous p.A194T mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). This 2-year-old female showed severe autosomal recessive SNHL with a mean hearing threshold of 87.5 dB HL.   Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the p.T123N variant of GJB2. The pathogenic potential of the p.T123N variant is controversial. Three variants of USH2A (NM_007123), R5143C, @VARIANT$, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (@GENE$) identified in SH 94-208).",4998745,GJB3;7338,ANK1;55427,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,C4870F;tmVar:p|SUB|C|4870|F;HGVS:p.C4870F;VariantGroup:24;CorrespondingGene:7399,0
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB6;4936,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (@VARIANT$) and TNNT2 (@VARIANT$), both sarcomeric genes. Here we reported heterozygous variants in genes that play roles in two different cardiomyocyte components; MYH7:part of the sarcomere, and LAMA4:part of the ECM/signalling component. To our knowledge, this is the first description of digenic mutations in MYH7 and LAMA4. The mutations were inherited from the parents, the mother carrying a @GENE$ mutation and with mild DCM, and a father carrying the @GENE$ variation but with a normal heart at age 29.",6359299,MYH7;68044,LAMA4;37604,Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB @VARIANT$ and @GENE$ p.R408C with SETX p.I2547T and SETX p.T14I).,4293318,ANG;74385,TAF15;131088,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,SCRIB;44228,FZD1;20750,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ @VARIANT$ (NM_000426, c.G2881A), @GENE$ @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,LAMA2;37306,KCNH2;201,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes.     ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the PDGFRB variant.",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"As mentioned above, some family members carrying heterozygous SCN5A @VARIANT$ mutation showed no evidence of cardiac events or cardiac diseases. The reason may be as follows: First, I:1 and II:2 who carried with the heterozygous @GENE$ p.R1865H presented no clinical syndromes because of incomplete penetrance or delayed onset. Moreover, gain-of-function mutation of SCN5A commonly induced LQTS, while loss-of-function mutation of SCN5A ordinary led to sinoatrial node dysfunction, atrioventricular block, atrial fibrillation and cardiomyopathy (e.g., ARVC/D; Blana et al.,; Han et al.,). Therefore, in this study, SCN5A p.R1865H may be the main cause of sinoatrial node dysfunction, whereas KCNH2 p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of @GENE$ @VARIANT$ and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and @GENE$/TACI C104R mutations. Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI @VARIANT$ mutations are shown.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"In subject 10035, a deleterious variant within the @GENE$ (Chr2) locus was identified in IMP4 (OMIM 612981; @VARIANT$, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in UBR4 (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and @GENE$ (OMIM 612496; rs144638812, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,DYT21;100885773,ARHGEF19;17710,rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,DCAF17;65979,FGFR1;69065,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"We found that @GENE$-@VARIANT$ was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants @GENE$-@VARIANT$ and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Functional testing of three @GENE$ variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation p.Cys238Arg, but no effect on transactivation activity on the @GENE$ promoter for GATA4 variants @VARIANT$ and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only Gly221 and Cys238 are close to Zn binding sites. The Gly221 is not directly involved in Zn binding but is situated next to Cys220 which binds the Zn atom, and therefore, the mutation Gly221Arg will disrupt the Zn binding, leading to a non-functional GATA4. The Cys238 binds Zn and its mutation to arginine leads to loss of Zn binding (Figure 4). GATA4 regulates the expression of multiple genes coding for hormones or components of the steroidogenic pathway during testis development and function. In Gata4ki mice with @VARIANT$ mutation interaction of Gata4 with cofactor Fog is abrogated, and consequently animals display anomalies of testis development.",5893726,GATA4;1551,CYP17;73875,p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463,0
"    Results We identified the digenic heterozygous mutations of @GENE$ @VARIANT$ (NM_001204798, @VARIANT$) and @GENE$ p.R1865H (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,0
"Co-transfection of HEK293 (human embryonic kidney) cells with plasmids encoding recombinant HA-TEK (hemagglutinin-tagged @GENE$) and GFP-CYP1B1 followed by co-immunoprecipitation with anti-GFP-conjugated beads demonstrated that HA-TEK and GFP-CYP1B1 are part of the same complex. As negative control, no interaction was detected between the GFP tag and HA-TEK proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ @VARIANT$ to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2).",5953556,TEK;397,CYP1B1;68035,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Conclusions Our study demonstrates that a novel mutation, @GENE$-@VARIANT$, dramatically impairs the IKr repolarizing current, whereas @GENE$-@VARIANT$, although previously reported to cause LQTS, probably exerts sub-pathogenic defects that are more consistent with a modifier allele.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas @GENE$-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
"   Conservation analyses at the mutant sites of @GENE$ and KCNH2 protein. SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and KCNH2 mutations. KCNH2 p.307_308del and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type @GENE$ (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b).",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 @VARIANT$, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of @GENE$, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of @GENE$, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,CELSR1;7665,SCRIB;44228,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663,0
"(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CAPN11;21392,UNC13B;31376,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Representative western blot and bar graph showing expression levels of SEC23A (A) and @GENE$ (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001.",4853519,MAN1B1;5230,GAPDH;107053,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Interestingly, four of these @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in @GENE$ (DCC)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in @GENE$ act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,DCC netrin 1 receptor;21081,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Both of which suggest that wild-type splicing would be affected     A recent study (Mazen et al., 2016) identified pathogenic variants in NR5A1 and @GENE$ in an individual with 46,XY gonadal dysgenesis, highlighting the possibility that digenic inheritance may play a role in the large phenotypic spectrum associated with NR5A1 variants. We also identified two patients with multiple affected diagnostic DSD genes (Table 3). Patient 3 was found to harbor a previously reported p.Arg84His variant in NR5A1, alongside a rare variant in ZFPM2 (c.A2107C, @VARIANT$, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in SRD5A2 (c.G680A, @VARIANT$, rs9332964:G>A) in Patient 11, who also harbored a single codon deletion at position 372 of @GENE$ (Table 3).",5765430,MAP3K1;8056,NR5A1;3638,p.Met703Leu;tmVar:p|SUB|M|703|L;HGVS:p.M703L;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681,0
"For example, the sequence homology between the human and mouse 23-amino acid sequence segment surrounding the @VARIANT$ was 95.7 percent (Fig. 3f). Sequencing of the VKORC1 gene did not disclose any pathogenic mutations.  Genotype/phenotype correlations A correlation of the clinical findings with the genotypes revealed that the proband and her sister were compound heterozygotes for the two GGCX missense mutations, potentially explaining their hematologic findings. In contrast, the proband's father, brother, her mother, and the mother's twin sister were heterozygous for one of the GGCX mutations only, designating them as carriers without clinical hematologic findings (Fig. 1g). The latter individuals were also carriers of the ABCC6 nonsense mutation p.R1141X. Specifically, the mother and her twin sister were heterozygous for the GGCX missense mutation p.V255M and the ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings. However, the proband's younger brother and father were heterozygous carriers of the p.S300F mutation in the @GENE$ gene while they also carried the p.R1141X mutation in the @GENE$ gene; they did not display any signs of cutaneous findings or hematologic disorder.",2900916,GGCX;639,ABCC6;55559,S300;tmVar:p|Allele|S|300;VariantGroup:16;CorrespondingGene:2677;RS#:121909684,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"In contrast to FGF inhibition, overexpression of @GENE$ attenuates the degradation of epidermal growth factor recepter (EGFR) and enhances downstream MAPK signalling (figure 3).    In patient AVM457, a de novo heterozygous missense variant c.3355G>A (@VARIANT$) with a robust deleterious damaging predictions (SIFT=0.1, PolyPhen2=0.99, GERP++=4.33, CADD=29.3) was identified in PREX2 (table 1). PREX2 activates PI3K signalling via inhibition of phosphatase and tensin homolog (PTEN), and both germline and mosaic @GENE$ variants are associated with AVMs.   In patient AVM427, the de novo heterozygous missense variant @VARIANT$ (p.Asp1148Tyr) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin.",6161649,IL17RD;9717,PTEN;265,p.Ala1119Thr;tmVar:p|SUB|A|1119|T;HGVS:p.A1119T;VariantGroup:5;CorrespondingGene:80243;RS#:1212415588,c.3442G>T;tmVar:c|SUB|G|3442|T;HGVS:c.3442G>T;VariantGroup:3;CorrespondingGene:9765,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in LRP6 (@VARIANT$, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in WNT10A (g.14712G>A, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B). Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,g.68531T>G;tmVar:g|SUB|T|68531|G;HGVS:g.68531T>G;VariantGroup:11;CorrespondingGene:4040,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in MYD88 gene and a homozygous splice-donor mutation (@VARIANT$) in @GENE$ gene. (D) Western Blot of CARD9 and MYD88 proteins performed on PBMC, EBVB, and PHA derived T cell lines. (E) TNFalpha production by monocytes after LPS stimulation (mean +- SEM of n = 2). (F) Phenotypic analysis of iDC and @GENE$ differentiated in vitro.",6383679,CARD9;14150,mDC;7529,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"   Missense variants in the NEFH gene were detected in four patients: the @VARIANT$ variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0
"In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD.  Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.2857A > G @VARIANT$) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G @VARIANT$) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature.",3975370,IL10RA;1196,IL10RB;523,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,p. S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the @GENE$ gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
Phenotype penetrance @GENE$-@VARIANT$ +/-@GENE$-@VARIANT$ +/-,5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and @GENE$ @VARIANT$), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR2;1078,FAT4;14377,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, @VARIANT$, p.L86F, p.F112S, @VARIANT$, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p. A85P;tmVar:p|SUB|A|85|P;HGVS:p.A85P;VariantGroup:78;CorrespondingGene:6012,p.R127L;tmVar:p|SUB|R|127|L;HGVS:p.R127L;VariantGroup:19;CorrespondingGene:2296;RS#:1085307884,0
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (p.N382S/@VARIANT$) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"  Digenic inheritances of GJB2/MITF and @GENE$/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB3;7338,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB6;4936,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"  This patient also was found to have a novel, heterozygous @GENE$ nonsense mutation @VARIANT$ not seen in 180 controls (Figure 1C; Table 1). Trp275 lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this G-protein coupled receptor, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in CHD7, FGF8, FGFR1, PROK2, @GENE$, TAC3, KAL1, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous @VARIANT$ (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;p.Thr478Ala from NP_056352).",3888818,TACR3;824,PROKR2;16368,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,c.1438A>G;tmVar:c|SUB|A|1438|G;HGVS:c.1438A>G;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,0
"@GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [@VARIANT$]) in TIMP3 were identified (online supplementary table S2).",6161649,SCUBE2;36383,VEGFR2;55639,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, @GENE$, APC, ZNRF3, @GENE$, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,RNF43;37742,LRP4;17964,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Our results indicate that the novel @GENE$-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-@VARIANT$, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Most of the identified variants were heterozygous, except for two homozygous @GENE$ mutations (i.e., @VARIANT$ and p.Arg1110Gln) detected in two patients. Most variants were included in the databases or reported in previous studies, except for one heterozygous variant in @GENE$ (i.e., @VARIANT$) that was novel.",8446595,DUOX2;9689,TSHR;315,p.Lys530*;tmVar:p|SUB|K|530|*;HGVS:p.K530*;VariantGroup:34;CorrespondingGene:50506,p. Ala579Val;tmVar:p|SUB|A|579|V;HGVS:p.A579V;VariantGroup:31;CorrespondingGene:7253,0
    CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in @GENE$ and a heterozygous missense variant c.190G>A(@VARIANT$) in @GENE$ (Table 2).,7549550,MYOD1;7857,MEOX1;3326,c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,1
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"He also had a KAL1 deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, @GENE$, @GENE$, GNRH1, or KISS1R.",3888818,TACR3;824,GNRHR;350,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Interestingly, four of these @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,1
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (p.R559W) and @GENE$: @VARIANT$ (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.7942G > A;tmVar:c|SUB|G|7942|A;HGVS:c.7942G>A;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,1
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
KCNH2 p.307_308del may affect the function of @GENE$ channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 @VARIANT$ and SCN5A @VARIANT$ by WES and predisposing genes analyses. More cellular and animal research is needed to further investigate whether the coexisting interaction of KCNH2 p.307_308del and @GENE$ p.R1865H increases the risk of the early-onset LQTS and sinoatrial node dysfunction.,8739608,Kv11.1;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,CELSR1;7665,FAT4;14377,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(Cys331Thr) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly). Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(@VARIANT$) variant in PKD1, while only one fetus inherited the p.(Arg872Gly) PKD2 variant.",7224062,PKD1;250,PKD2;20104,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Ser872Gly;tmVar:p|SUB|S|872|G;HGVS:p.S872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"GJB2 Single Heterozygotes where @GENE$ was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (rs121908073), and a novel variant, @VARIANT$ of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,DFNB1;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.W482R;tmVar:p|SUB|W|482|R;HGVS:p.W482R;VariantGroup:0;CorrespondingGene:117531;RS#:754142954;CA#:5081956,0
"DUOX2 and @GENE$ mutation locations varied in the corresponding proteins (Figure 2). Additionally, three DUOXA2 variants were found in 3/21 patients (14%), and a known heterozygous variant in SLC26A4 was found in one patient. No mutations in SLC5A5, TPO, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient.",6098846,TG;2430,DUOXA2;57037,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"a, b Pedigree chart of the patients carrying mono-allelic @GENE$ and @GENE$ mutations. c Audiograms of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 @VARIANT$ mutations.",7067772,EPHA2;20929,SLC26A4;20132,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (c.229C>T; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.    Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, rs143224912 in @GENE$ and @VARIANT$ in S100A3, and one novel variant in @GENE$, were identified.",6637284,SETDB1;32157,S100A13;7523,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"The novel MYO6 @VARIANT$ variant segregated with hearing loss in all but one individual (V-5) who displayed clinically unconfirmed mild hearing loss (Fig. 1a). Supplemental Table S4 summarizes variant annotation and classification.       Discussion Congenital neutropenia and monocytosis due to GFI1 variants was first reported in 2003, following the observation that GFI1-deficient mice were unexpectedly neutropenic. GFI1 encodes a zinc finger transcriptional repressor oncoprotein. The @VARIANT$ variant occurs in a highly evolutionarily conserved region of the @GENE$ protein (Supplemental Figure S1). In vitro studies demonstrated that the variant acted in a dominant negative manner, abolishing DNA binding and hence repressor activity of the protein. Interestingly, GFI1 recruits to chromatin the enzyme lysine-specific demethylase-1 (LSD1); pharmacologic inhibition of @GENE$ or genetic knock-down of LSD1 skews granulocyte-monocyte progenitor differentiation resulting in neutropenia and monocytosis as seen in this family.",7026993,GFI1;3854,LSD1;32240,I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,CAPN11;21392,MYOD1;7857,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein. However, the two rare FUS variants (@VARIANT$ and P106L) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein.",6707335,SPG11;41614,ubiquilin-2;81830,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,Y25C;tmVar:p|SUB|Y|25|C;HGVS:p.Y25C;VariantGroup:12;CorrespondingGene:2521;RS#:141516414;CA#:8023442,0
"The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(Ser123Thr), and a second variant in @GENE$, p.(@VARIANT$).",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, @GENE$, GSK3, CK1, APC, BCL9, and @GENE$) as well.",7877624,ROR2;55831,BCL9L;65615,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"He also had a KAL1 deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the @GENE$ protein encoded by KAL1 (Figure S1C,D). The KS proband with @GENE$/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,anosmin-1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein. However, the two rare FUS variants (Y25C and P106L) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein. Although the majority of FUS mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging.       In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel @VARIANT$ deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The NEK1 @VARIANT$ variant was also present in this patient.",6707335,ubiquilin-2;81830,FUS;2521,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,0
"Since the changes were in the DNA interaction sites, it is expected that both @VARIANT$ and p@VARIANT$ mutations could have altered binding and activation of some of @GENE$ interaction partners and could also bind to other promoters and potentially change the transcription of several other genes.       In fact, we found segregating genetic variants besides GATA4 in cases 2 and 3 using NGS. In one 46,XY DSD subject without CHD, a heterozygote variant in LRP4 gene was found. Mutations in @GENE$ have been related to the Cenani-Lenz syndactyly syndrome and disruption of canonical WNT/beta-catenin signaling (OMIM 604270), which is not only important in bone formation but also in sexual development.",5893726,GATA4;1551,LRP4;17964,p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"GJB2 Single Heterozygotes where @GENE$ was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (@VARIANT$), and a novel variant, p.W482R of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1).",4998745,DFNB1;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,rs121908073;tmVar:rs121908073;VariantGroup:11;CorrespondingGene:117531;RS#:121908073,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,gap junction protein beta 3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, @VARIANT$), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, @VARIANT$) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS.",8739608,KCNH2;201,SCN5A;22738,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,c.A3083T;tmVar:c|SUB|A|3083|T;HGVS:c.3083A>T;VariantGroup:5;CorrespondingGene:3757,0
"The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the SLC20A2 mutation and secondarily from the PDGFRB variant. Currently, the genetic basis for the clinical heterogeneity of PFBC is not largely understood, and it cannot be explained only by a single variant. PFBC patients with biallelic variants in SLC20A2 have been reported. In 2012, Wang et al. reported that PFBC patients with compound heterozygous @GENE$ mutations (@VARIANT$, p.Ser121Cys and c.1802C>G, p.Ser601Trp) presented extremely severe brain calcification, accompanied by repetitive seizures, mental retardation, and developmental delay since infancy (Wang et al., 2012, 2015).",8172206,PDGFRB;1960,SLC20A2;68531,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.362C>G;tmVar:c|SUB|C|362|G;HGVS:c.362C>G;VariantGroup:3;CorrespondingGene:6575,0
"Except for the @GENE$ gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, @GENE$, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,SEMA7A;2678,PLXNA1;56426,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ @VARIANT$, SCRIB p.G1108E, SCRIB @VARIANT$ and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in @GENE$ (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, @GENE$, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well. No potentially pathogenic rare variant was identified. In order to identify variant(s) in other genes which might influence the expressivity of WS phenotype in our cases, exome data was filtered by using an unbiased and hypothesis-free approach. A rare missense variant (@VARIANT$; p.Val34Gly) in the C2orf74 gene was identified in both affected individuals.",7877624,TYRO3;4585,ZNRF3;46592,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,VPS13C;41188,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"He had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, KAL1, GNRHR, @GENE$, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous @VARIANT$ (p.Thr480Ala) @GENE$ variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;p.Thr478Ala from NP_056352). Since Thr478 was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease.",3888818,GNRH1;641,NELF;10648,c.1438A>G;tmVar:c|SUB|A|1438|G;HGVS:c.1438A>G;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0
"   The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on @GENE$ interaction and internalization was examined. While the amount of co-precipitated @GENE$ mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,EphA2;20929,pendrin;20132,Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"No significant change was observed with HA-TEK G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-@GENE$ proteins E103D and @VARIANT$ exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and @VARIANT$ showed perturbed interaction with HA-TEK.",5953556,CYP1B1;68035,TEK;397,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Using a Bonferonni-corrected significance level of 8.2x10-4, 3 variants were significantly more common in our ALS discovery cohort (rs3739927 and @VARIANT$ in @GENE$, and @VARIANT$ in @GENE$).",4293318,SETX;41003,EWSR1;136069,rs882709;tmVar:rs882709;VariantGroup:27;CorrespondingGene:23064;RS#:882709,rs41311143;tmVar:rs41311143;VariantGroup:21;CorrespondingGene:2130;RS#:41311143,0
"For example, two variants in proband P15, @VARIANT$ in @GENE$ and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while @GENE$ p. Gln1626His variant was inherited from unaffected mother.",8152424,PROKR2;16368,DMXL2;41022,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form.",6707335,GRN;1577,SIGMAR1;39965,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Myopathy With @GENE$ and @GENE$ Variants: Clinical and Pathological Features Objective The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Patients and methods Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, @VARIANT$) and a heterozygous variant in TIA1 (@VARIANT$, p.Asn357Ser).",5868303,SQSTM1;31202,TIA1;20692,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"As shown in Table 3, all male individuals carrying the @GENE$-@VARIANT$ mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant @GENE$-@VARIANT$ showed the ERS phenotypes.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"    Sanger sequencing Sanger sequencing was performed on available samples for confirmation of GFI1 and @GENE$ variants in family members to perform segregation analysis. Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in @GENE$ (@VARIANT$/c.1145A > G) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,MYO6;56417,GFI1;3854,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23A@VARIANT$/M400I MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. GAPDH was used as an internal control. ***, P < 0.001. The R334C mutation in MAN1B1 was previously demonstrated to result in a decreased level of MAN1B1 protein; and we found that this was the case in fibroblasts from affected patients (P < 0.001, ANOVA) (Fig. 3B; Supplemental Fig. S4B). A significant decrease in MAN1B1 level was also observed in fibroblasts with heterozygous mutations in both SEC23A and @GENE$ (P < 0.001, ANOVA) when compared with wild-type and @GENE$ heterozygous fibroblasts (Fig. 3B).",4853519,MAN1B1;5230,SEC23A;4642,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"@VARIANT$ carriers required different surgical procedures for correct IOP control (Table 2). This nucleotide substitution also mapped at FOXC2-@GENE$ intron 1 (@VARIANT$) and the regulatory feature (promoter) (Fig 1C), and it was inferred to produce a low functional effect on @GENE$ and a modifier outcome on both FOXC2-AS1 and the overlapping promoter.",6338360,AS1;736,FOXC2;21091,p.(S36S);tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260,n.145+174G>A;tmVar:n|SUB|G|145_174|A;VariantGroup:14;CorrespondingGene:5729,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"GJB2 Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected @GENE$ Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (rs121908073), and a novel variant, @VARIANT$ of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.W482R;tmVar:p|SUB|W|482|R;HGVS:p.W482R;VariantGroup:0;CorrespondingGene:117531;RS#:754142954;CA#:5081956,1
"Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,1
"Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys).",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,TANK-binding kinase 1;22742,OPTN;11085,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In addition, 2 genes presented variants in 3 patients: MAML3 (patients 6, 7 and 8) and @GENE$ (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and @GENE$ variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,NOTCH1;32049,MAML3;41284,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.",4470809,TBK1;22742,OPTN;11085,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,CCNF;1335,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The c.229C>T (@VARIANT$) variant in S100A3 and @VARIANT$ (p.I80Gfs*13) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2.             Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, S100A13 and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.",6637284,S100A13;7523,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). The c.1787A>G (@VARIANT$) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ c.1200G>C (@VARIANT$) and @GENE$ c.1000C>T (@VARIANT$), associated with congenital birth defects in two patients from a consanguineous family.",4853519,SEC23A;4642,MAN1B1;5230,p.M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,p.R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1
"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ A115P and GFP-CYP1B1 @VARIANT$ to immunoprecipitate HA-@GENE$ @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 @VARIANT$), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD6;2617,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0
"In the individual carrying the @VARIANT$ @GENE$ variant, an additional novel alteration (@VARIANT$) was detected in the @GENE$ gene.",6707335,NEFH;40755,GRN;1577,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,1
"A concomitant variant (@VARIANT$, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This SCN5A-R1193Q variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).    Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (@VARIANT$, p.Q1916R) in CACNA1C.",5426766,CACNA1C;55484,SCN5A;22738,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,c.5747A>G;tmVar:c|SUB|A|5747|G;HGVS:c.5747A>G;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"    CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in MYOD1 and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.",7549550,MEOX1;3326,MYOD1;7857,c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"Its numerous domains allow @GENE$ to serve as a frame for multiprotein complexes and regulator of ubiquitinated protein turnover. SQSTM1 mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in LRP6 (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B). Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, @VARIANT$), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (WNT10A c.637G>A, rs147680216) in EAS.",8621929,WNT10A;22525,LRP6;1747,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,rs2302686;tmVar:rs2302686;VariantGroup:2;CorrespondingGene:4040;RS#:2302686,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, @VARIANT$ and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,c.475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"These phenomenon indicate that the mutated @GENE$-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. @GENE$-@VARIANT$ (p.Ala338Val) variant impaired the catabolism of ADMA in EA.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Other family members who have inherited TCF3 T168fsX191 and @GENE$/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (@VARIANT$) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 @VARIANT$ mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 T168fsX191 gene. Exons coding E2A functional domains, activation domain 1 and 2 (AD1, @GENE$) and helix-loop-helix (HLH) domains are shown.",5671988,TNFRSF13B;49320,AD2;30951,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Here, we have demonstrated that the TCF3 @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the @GENE$/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family. Hence, priority should be given to identifying the @GENE$ T168fsX191 mutation for preimplantation genetic diagnosis and/or chorionic villus sampling.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"(E) The @GENE$ mutation c.466C>T and WNT10A mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in EDA and c.511C>T in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,0
"The novel truncated variant in @GENE$ was not found in our ""in-house"" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The c.229C>T (@VARIANT$) variant in @GENE$ and @VARIANT$ (p.I80Gfs*13) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.",6637284,S100A13;7523,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Among the 18 variants, three missense variations, the new @GENE$ mutation (@VARIANT$) and the known @GENE$ missense variants (@VARIANT$ and G351R), caught our attention: we hypothesized that these three variants might together contribute to an increased risk of developing early onset IBD.",3975370,NOD2;11156,IL10RA;1196,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,1
"Therefore, in this study, @GENE$ p.R1865H may be the main cause of sinoatrial node dysfunction, whereas KCNH2 @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ p.307_308del and SCN5A @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$).",6610752,KCNH2;201,LQT6;71688,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Additionally, a novel variant (@VARIANT$) in the 5' untranslated region of the FUS gene was also detected. As the screening of untranslated regions was not in the scope of our research, we did not examine it further.   No SOD1 and TARDBP gene variants were found in this cohort. We would like to point out that 37 of the analyzed samples were overlapping samples from a previous study and were known to be negative for SOD1 and @GENE$ mutations. Still, based on earlier results, one would expect to detect SOD1 variants in the further 70 samples. Variants Detected in Minor ALS Genes By focusing on the analysis of minor ALS genes, 33 variants (31 missense and 2 splicing) were detected in 26 genes corresponding to 29 patients (27.1% of all patients,  Supplementary Table 2 ). No patients were identified as being homozygous for any of the detected variants. A patient was carrying two novel variants (T2583I and @VARIANT$) in the @GENE$ gene; both variants localized in the motor domain of the protein.",6707335,TARDBP;7221,DYNC1H1;1053,c.-25C > T;tmVar:c|SUB|C|-25|T;HGVS:c.-25C>T;VariantGroup:38;CorrespondingGene:2521,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"GJB2 Single Heterozygotes where @GENE$ was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (@VARIANT$), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,DFNB1;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,rs121908073;tmVar:rs121908073;VariantGroup:11;CorrespondingGene:117531;RS#:121908073,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and TAF15 p.R408C with SETX @VARIANT$ and @GENE$ p.T14I).,4293318,VAPB;36163,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"No mutations in SLC5A5, @GENE$, or @GENE$ gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: @VARIANT$ (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,TPO;461,IYD;12352,c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (c.2686C>T, @VARIANT$) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"In our study, @VARIANT$(p. Arg631*) and c.1267C > T(@VARIANT$) were the two reported variants, while c.1525delA(p. Ser509fs) and c.1524del A(p. Ser509fs) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of @GENE$ gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function.         @GENE$ (PROK2) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2.",8796337,KAl1;55445,Prokineticin-2;9268,c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223,p. Arg423*;tmVar:p|SUB|R|423|*;HGVS:p.R423*;VariantGroup:7;CorrespondingGene:3730,0
"Two unaffected subjects, SH60-137 and SH60-139, also carried @VARIANT$ in WFS1. This indicates that neither p.R143W in GJB2 nor p.D771N in WFS1 contributed to SNHL in SH60-136 and that p.R143W in GJB2 was an incidentally detected variant in this subject. @GENE$ = gap junction protein beta 2, SNHL = sensorineural hearing loss, WFS1 = wolfram syndrome 1.             Single Heterozygous GJB2 Mutant Allele Possibly Contributing to Deafness via Digenic Inheritance: Double Heterozygosity with Additional Mutation in Other Deafness Genes (Group II) Interestingly, two subjects (SH107-225 and SH175-389) showed double heterozygosity for a GJB2 mutation and another likely pathogenic mutation in another deafness gene. We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, p.R341C, in one of the @VARIANT$ carriers (SH107-225) (Figure 4A).",4998745,GJB2;2975,MITF;4892,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
"Moreover, the MAF of @GENE$-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and @GENE$-@VARIANT$ were much larger (0.187 and 0.352, respectively).",5578023,KCNQ1;85014,KCNE1;3753,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Sequence alterations were detected in the COL6A3 (@VARIANT$), @GENE$ (rs143445685), CAPN3 (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,RYR1;68069,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,CELSR1;7665,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors.",3842385,EDA;1896,WNT10A;22525,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a).,2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
A male (ID104) was found to have a heterozygous missense variant @VARIANT$ (p.Lys330Met) in EHMT1 and a missense variant @VARIANT$ (p.Leu593Val) in @GENE$. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases.,7463850,SLC9A6;55971,EHMT1;11698,c.989A > T;tmVar:c|SUB|A|989|T;HGVS:c.989A>T;VariantGroup:1;CorrespondingGene:79813;RS#:764291502;CA#:5375151,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,0
"In this family, the patient (II: 1) with digenic heterozygous mutations of KCNH2 p.307_308del and SCN5A @VARIANT$ presented the earliest phenotype of LQTS, and she suffered from syncope, torsades de pointes, and ventricular fibrillation more frequently at rest, whereas the members (I:1 and II:2) without KCNH2 @VARIANT$ showed normal QT intervals and cardiac function. The changed site of KCNH2 p.307_308 was highly conserved across most species, suggesting p.307_308 of @GENE$ protein playing a significant role in function. The result indicated that the novel genetic background, KCNH2 p.307_308del, may affect and even induce the phenotype of LQTS. The predictions of the RNA secondary structure and physical-chemical parameters showed KCNH2 p.307_308del affected the single-stranded RNA folding, and subsequently and significantly weaken the hydrophobicity of mutant amino acid residues, which indicated that KCNH2 mutation probably played a dominant hereditary role in the occurrence of LQTS in this proband.                SCN5A gene is located in chromosome 3p22.2, encoding the alpha subunit of the voltage-gated sodium channel (@GENE$) in human cardiomyocytes (Li et al.,).",8739608,KCNH2;201,Nav1.5;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB6;4936,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"  Digenic inheritances of @GENE$/MITF and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,GJB2;2975,GJB3;7338,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), @GENE$ (c.46C>G; @VARIANT$) and @GENE$ (c.9921T>G).",3125325,USH1G;56113,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"These mutations are expected to affect the three classes of @GENE$ isoforms (Tables 2, 3, Figure 1). Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (@VARIANT$), a novel nucleotide deletion (@VARIANT$; p.E2135fsX31), and six missense mutations, four of which (p.R1189W, p.R1379P, p.D2639G, and p.R3043W) had not been previously reported.",3125325,harmonin;77476,CDH23;11142,c.6050-9G>A;tmVar:c|SUB|G|6050-9|A;HGVS:c.6050-9G>A;VariantGroup:172;CorrespondingGene:64072;RS#:367928692;CA#:261794,c.6404_6405delAG;tmVar:c|DEL|6404_6405|AG;HGVS:c.6404_6405delAG;VariantGroup:207;CorrespondingGene:65217,0
"This genetic synergism is also supported by the potential digenic inheritance of LRP6 and @GENE$ mutations in Family 4. The proband, who had @GENE$ p.(@VARIANT$), p.(Ser127Thr), and WNT10A p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,WNT10A;22525,LRP6;1747,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in  Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, @GENE$, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for EVC, FGF10, GLI2, RIPK4 and EYA1; and RET for PIK3R3 with @GENE$, which also is connected with RIPK4.",6726737,FGF10;3284,PTPN11;2122,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, DFNB3, and @GENE$, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES.",4998745,DFNB16;15401,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"This analysis indicated that the CAPN3 variant c.1663G>A (rs138172448), which results in a @VARIANT$ change, and the DES gene variant @VARIANT$ (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the @GENE$ and @GENE$ genes, through digenic inheritance, are the cause of the myopathy in this patient.",6180278,CAPN3;52,DES;56469,p.Val555Ile;tmVar:p|SUB|V|555|I;HGVS:p.V555I;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,c.656C>T;tmVar:c|SUB|C|656|T;HGVS:c.656C>T;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,1
"However, significantly more pro-COL1A1 was secreted in fibroblasts with heterozygous mutations in both SEC23A and @GENE$ (P < 0.05, ANOVA), when compared with wild type (Supplemental Fig. S7). Surprisingly, mutant fibroblasts showed levels of intracellular and secreted pro-COL1A1 comparable with those of wild-type cells. Our data indicate that a normal level of MAN1B1 is required to prevent secretion of abnormally folded pro-COL1A1. These data also indicate that an alternate pathway is used for quality control of pro-COL1A1 when MAN1B1 alpha-mannosidase activity is reduced. DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in @GENE$, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet.",4853519,MAN1B1;5230,SEC23A;4642,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"On the contrary, the functionality of the @GENE$-@VARIANT$ channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. On the contrary, in the mother, some other factors, including unknown genetic modifiers, could counteract the functional impairment of mutant channels, thereby protecting the asymptomatic @GENE$-@VARIANT$ mutation-positive subject from arrhythmia susceptibility.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"He had no mutations in @GENE$, FGF8, FGFR1, PROK2, PROKR2, TAC3, @GENE$, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to @VARIANT$ ;p.Thr478Ala from NP_056352). Since Thr478 was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease.",3888818,CHD7;19067,KAL1;55445,c.1432A>G;tmVar:c|SUB|A|1432|G;HGVS:c.1432A>G;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0
"However, none of these signs were evident from metabolic work of the patient with @GENE$ L718F, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and @GENE$ @VARIANT$ variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the RYR1 p.T4823 M variant in MH. Subject R462 was diagnosed as MHS, which appeared to correlate with CACNA1S @VARIANT$, previously reported in a single MHS subject.",6072915,PHKA1;1981,NDUFS8;1867,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0
"At the molecular level, @GENE$ mediates cell-cell adhesion by regulating PI3K/@GENE$ signalling (figure 3).      In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (@VARIANT$) was identified in IL17RD (table 1).",6161649,N-cadherin;20424,Akt;3785,c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588,p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB2;2975,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"In patient AVM558, the de novo heterozygous missense variant c.1694G>A (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in @GENE$/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/@GENE$ signalling (figure 3).      In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (p.Gly226Ser) was identified in IL17RD (table 1).",6161649,BMP;55955,Akt;3785,c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588,0
"The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in @GENE$. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly).",7224062,PKD2;20104,PKD1;250,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,1
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene @GENE$ were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Myopathy With @GENE$ and @GENE$ Variants: Clinical and Pathological Features Objective The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Patients and methods Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (@VARIANT$, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, @VARIANT$).",5868303,SQSTM1;31202,TIA1;20692,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,CDH23;11142,MYO7A;219,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"This analysis indicated that the @GENE$ variant c.1663G>A (@VARIANT$), which results in a p.Val555Ile change, and the @GENE$ gene variant @VARIANT$ (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging.",6180278,CAPN3;52,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,c.656C>T;tmVar:c|SUB|C|656|T;HGVS:c.656C>T;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (@VARIANT$), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: @VARIANT$, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,DNAH17;72102,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"Moreover, this @GENE$ variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/MITF and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,MITF;4892,gap junction protein beta 6;4936,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Mutations in @GENE$ and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"In Family F, the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/GJB3, while the mother is heterozygous for the @GENE$/@VARIANT$ (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,0
  LIMITATIONS Our study was performed only in the statistical field on @GENE$ p.307_308del and SCN5A p.R1865H by WES and predisposing genes analyses. More cellular and animal research is needed to further investigate whether the coexisting interaction of KCNH2 @VARIANT$ and @GENE$ @VARIANT$ increases the risk of the early-onset LQTS and sinoatrial node dysfunction.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"          Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the GGCX and @GENE$ genes. The results demonstrated the presence of two missense mutations in @GENE$. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a valine by methionine at position 255 (@VARIANT$) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b).",2900916,VKORC1;11416,GGCX;639,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"    Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and WNT10A mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"A nonsense variant in @GENE$ (NM_000625.4: @VARIANT$, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs. ATP2A3 is highly expressed in cerebellar Purkinje cells (Allen Brain Atlas) and is a member of the P-type ATPase superfamily that includes the gene (@GENE$) causally associated with rapid-onset dystonia-Parkinsonism (DYT12).",6081235,NOS2;55473,ATP1A3;113729,c.2059C>T;tmVar:c|SUB|C|2059|T;HGVS:c.2059C>T;VariantGroup:11;RS#:200336122,p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a @VARIANT$ of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,Cx31;7338,GJB2;2975,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"GJB2 Single Heterozygotes where @GENE$ was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (@VARIANT$) (rs121908073), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,DFNB1;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,c.100C>T;tmVar:c|SUB|C|100|T;HGVS:c.100C>T;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002,0
"The most common mutation was @VARIANT$ (@GENE$: c.3329G>A), which was found in 5 patients, accounting for 11% of all the cases. Of the 3 novel variants in DUOX2, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and p.D137E and p.E389K were missense mutations located in the peroxidase-like domain (Fig. S3A).  A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, DUOX2, DUOXA2 and TPO).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B).",7248516,DUOX2;9689,SLC26A4;20132,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:12;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"    Sanger sequencing Sanger sequencing was performed on available samples for confirmation of GFI1 and @GENE$ variants in family members to perform segregation analysis. Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,MYO6;56417,GFI1;3854,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and @VARIANT$; p.Trp275X of TACR3).,3888818,TACR3;824,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
A male (ID104) was found to have a heterozygous missense variant @VARIANT$ (p.Lys330Met) in @GENE$ and a missense variant c.1777C > G (@VARIANT$) in @GENE$. Limited clinical information was available about this male.,7463850,EHMT1;11698,SLC9A6;55971,c.989A > T;tmVar:c|SUB|A|989|T;HGVS:c.989A>T;VariantGroup:1;CorrespondingGene:79813;RS#:764291502;CA#:5375151,p.Leu593Val;tmVar:p|SUB|L|593|V;HGVS:p.L593V;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,1
"25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the @GENE$ (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS. 21  @GENE$ promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors.",7689793,CAPN9;38208,TRIP6;37757,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"The c.1592G>A (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in @GENE$/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant c.2075A>G (p.Asn692Ser) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, @GENE$ mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).",6161649,BMP;55955,N-cadherin;20424,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,ATP2A3;69131,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"A PCR amplicon containing GNRHR exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (@VARIANT$), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (c.[238C > T];[=]) (@VARIANT$) in the @GENE$ gene.         The @GENE$ frameshift mutation was identified in two different families and has not been reported before.",5527354,PROKR2;16368,GNRHR;350,rs373270328;tmVar:rs373270328;VariantGroup:0;CorrespondingGene:2798;RS#:373270328,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L @GENE$ proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,1
"Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and p.(H395N); @GENE$: @VARIANT$). In summary, the increased frequency in PCG patients of rare @GENE$ and PITX2 variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,PITX2;55454,FOXC2;21091,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,CCNF;1335,ALS2;23264,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,TOR2A;25260,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, @VARIANT$, p.Tyr27His), MBD5 (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, @VARIANT$, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
One IHH patient had compound heterozygous NELF mutations (@VARIANT$ and c.629-23G>C); and he did not have mutations in 11 other known IHH/KS genes. Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3). In vitro evidence of these @GENE$ mutations included reduced protein expression and splicing defects.,3888818,KAL1;55445,NELF;10648,c.629-21C>G;tmVar:c|SUB|C|629-21|G;HGVS:c.629-21C>G;VariantGroup:4;CorrespondingGene:26012;RS#:768001142;CA#:5370502,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The DNA sequencing chromatograms from the proband show two LRP6 and one @GENE$ heterozygous mutations. While both @GENE$ variants, p.(@VARIANT$) and p.(Asn1075Ser), were inherited from her father, the WNT10A mutation, @VARIANT$ was maternally derived.",8621929,WNT10A;22525,LRP6;1747,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"His cells produced higher levels of IgG and IgM than his mother (II.2, who bears both the @GENE$/TACI @VARIANT$ and @GENE$ @VARIANT$ mutations).",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"However, it was hard to determine whether the coexisting interactions of @GENE$ @VARIANT$ and SCN5A @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while @GENE$ mutation was only associated with sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"The @GENE$ R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with @GENE$ variants (L106V and @VARIANT$). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form.",6707335,NEK1;14376,CCNF;1335,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of @GENE$. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,DFNB1;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
" In patient AVM206, the de novo heterozygous missense variant c.2075A>G (@VARIANT$) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).      In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (p.Gly226Ser) was identified in @GENE$ (table 1).",6161649,CDH2;20424,IL17RD;9717,p.Asn692Ser;tmVar:p|SUB|N|692|S;HGVS:p.N692S;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"    Results We identified the digenic heterozygous mutations of @GENE$ @VARIANT$ (NM_001204798, c.921_923del) and @GENE$ @VARIANT$ (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1
"   Figures Evidence for digenic inheritance of deafness involving GJB2 and @GENE$. Pedigree and segregation of the mutations in GJB2 and GJB3 The deaf proband is indicated by an arrow. GJB2/GJB3 genotypes are given below the respective pedigrees symbol (a, f and k). Direct sequence analysis showing the @VARIANT$ mutation (b and g) and wild type (WT) allele (c and h) of GJB2. Direct sequence analysis showing the 299-300delAT mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the @VARIANT$ (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of Cx31 and Cx26 in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against @GENE$ (a) and Cx31 (b).",2737700,GJB3;7338,Cx26;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,497A>G;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Protein structure analysis We performed protein structure analysis on the two WNT10A mutations (p.R171C and @VARIANT$) and two novel @GENE$ mutations (@VARIANT$ and p.I312M) that were identified in this study. For WNT10A, the conservation of residues in sequences was determined to predict the influence of the two mutations. The sequences of orthologs of human WNT10A protein were retrieved from the KEGG database; these sequences were used to perform sequence alignment with ClustalX2.0.12. PsiPred 3.0 was used to predict the 2D structure of human @GENE$ protein.",3842385,EDA;1896,WNT10A;22525,p.G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and @VARIANT$; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"(A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and WNT10A mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"    Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,TOR2A;25260,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 @VARIANT$, DVL3 p.R148Q, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,PTK7;43672,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and @GENE$.       3.5. Predicted Structural Alterations and Pathogenicity of LRP6 Missense Mutations Computational prediction of the structural impact for the five LRP6 missense mutations on protein stability demonstrated that p.Met168Arg, @VARIANT$, and @VARIANT$ were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively.",8621929,LRP6;1747,WNT10A;22525,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,CDH23;11142,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,1
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and @GENE$ p.R408C with @GENE$ @VARIANT$ and SETX p.T14I).,4293318,TAF15;131088,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (p.Gln106Arg, at 0.2%; p.Val134Gly, at 0.0008%; @VARIANT$ at 0.2%; and @GENE$ @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (@GENE$/PROKR2) heterozygous mutation.",5527354,PROKR2;16368,GNRHR;350,p.Arg262Gln;tmVar:p|SUB|R|262|Q;HGVS:p.R262Q;VariantGroup:5;CorrespondingGene:2798;RS#:104893837;CA#:130198,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,MYO7A;219,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 6;4936,GJB2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Coimmunoprecipitation analysis indicated an interaction between wild-type @GENE$ and wild-type @GENE$, which did not exist between @VARIANT$ FLNB and @VARIANT$ OFD1 (figure 3D).",7279190,OFD1;2677,FLNB;37480,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,1
"Six variants in PKD1 occurred de-novo, three of which were not previously described: c.3236del p.(Asp1079Alafs*25), @VARIANT$ p.(Glu2954*), and @VARIANT$. One de-novo and novel variant was also detected in PKD2: c.992G>A p.(Cys331Tyr). Types of 158 distinct possible pathogenic variants detected in @GENE$ and @GENE$ genes.",7224062,PKD1;250,PKD2;20104,c.8860G>T;tmVar:c|SUB|G|8860|T;HGVS:c.8860G>T;VariantGroup:46;CorrespondingGene:5310,c.9201+1G>A;tmVar:c|SUB|G|9201+1|A;HGVS:c.9201+1G>A;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,0
"Analysis of the data for variants in genes associated with non-syndromic hearing loss (Supplemental Table S3), identified a novel single nucleotide variant in @GENE$ (NM_004999.4, c.3526A > C/p.Ile1176Leu, @VARIANT$) (Fig. 1b, right panel), a gene that has previously been associated with AD hearing loss. The novel MYO6 I1176L variant segregated with hearing loss in all but one individual (V-5) who displayed clinically unconfirmed mild hearing loss (Fig. 1a). Supplemental Table S4 summarizes variant annotation and classification.       Discussion Congenital neutropenia and monocytosis due to GFI1 variants was first reported in 2003, following the observation that @GENE$-deficient mice were unexpectedly neutropenic. GFI1 encodes a zinc finger transcriptional repressor oncoprotein. The @VARIANT$ variant occurs in a highly evolutionarily conserved region of the GFI1 protein (Supplemental Figure S1).",7026993,MYO6;56417,GFI1;3854,I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,0
"   The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"G112A (p.G38S) variant has been reported to reduce @GENE$ and @GENE$ channel currents, enhance KCNH2 susceptibility to QT-prolonging factors, and increase the risk for LQTS, atrial fibrillation, and heart failure. Bioinformatic analysis predicted that KCNE1-G38S was ""tolerated"" and KCNH2-C108Y was ""damaging"", whereas divergent results were obtained for KCNQ1-R583H and KCNH2-K897T, i.e., some programs considered these variants ""damaging"" and others as ""benign"" (Table 2). Moreover, the MAF of KCNQ1-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and KCNE1-@VARIANT$ were much larger (0.187 and 0.352, respectively).",5578023,KCNH2;201,KCNQ1;85014,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,FGFR1;69065,DCC;21081,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,1
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, @VARIANT$) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Mutations in @GENE$ and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 @VARIANT$ may affect the function of @GENE$ channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and @GENE$ p.R1865H by WES and predisposing genes analyses.",8739608,Kv11.1;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). The c.1787A>G (@VARIANT$) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"The proband, who had @GENE$ p.(Asn1075Ser), p.(Ser127Thr), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. The LRP6 p.(@VARIANT$) mutation substitutes highly-conserved asparagine with serine, which is predicted to destabilize the protein structure.",8621929,LRP6;1747,WNT10A;22525,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including @GENE$ may modulate the WS2 phenotype in WS2 cases with MITF mutation.",7877624,MITF;4892,LEF-1;7813,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"He also had a KAL1 deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by @GENE$ (Figure S1C,D). The KS proband with @GENE$/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"These two individuals were heterozygous carriers of p.R1141X mutation in ABCC6 and @VARIANT$ in GGCX. Since heterozygous carriers of @VARIANT$ in @GENE$ alone do not manifest PXE and @GENE$ mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance.",2900916,ABCC6;55559,GGCX;639,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"The proband of Family 3 was a compound heterozygote of p.(@VARIANT$) and p.(@VARIANT$) mutations and had fourteen missing teeth, while his father, who carried the p.(Ala754Pro) mutation, exhibited only two. Interestingly, the mother was homozygous for the p.(Ser127Thr) mutation and had all permanent teeth excepting third molars, suggesting that the variant might serve as a putative genetic modifier while not being disease-causing itself. These observations of digenic inheritance and genetic modification are supported by the significant role of @GENE$ signaling in tooth development and a direct molecular interaction between @GENE$ and LRP6.",8621929,WNT;22529,WNT10A;22525,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,0
"The @VARIANT$ substitution might cause conformational changes within the Cx31 molecule or affect the ability of Cx31 to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the Cx26 mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, @VARIANT$, F191L, and A197S in Cx26 as well as F193C, S198F and G199R in @GENE$, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the @GENE$ gene except for the EC2 and TM4 domains, which are main domains for deafness mutations.",2737700,Cx32;137,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,R165W;tmVar:p|SUB|R|165|W;HGVS:p.R165W;VariantGroup:5;CorrespondingGene:2706;RS#:376898963;CA#:180672,0
"Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with @GENE$. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between p.R2003H FLNB and @VARIANT$ OFD1 (figure 3D).  FLNB and OFD1 variants in individuals with AIS. (A) Pedigree of AIS twins. Case 98-73 (proband) is indicated with an arrow. (B) Protein sequences around FLNB. p.R2003 in 11 species. (C) Local view of in silico structure analysis of the WT and mutant FLNB structures (variant H2003). The WT structure of FLNB is shown in purple, and the mutant structure of @GENE$ is shown in green. The side chains of R/@VARIANT$ are shown as sticks, and the other residues are shown as lines.",7279190,OFD1;2677,FLNB;37480,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,H2003;tmVar:H2003;VariantGroup:31;CorrespondingGene:2317,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,Cx26;2975,GJB6;4936,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Patient P0432 has a @VARIANT$ (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; p.L16V) and @GENE$ (c.9921T>G).",3125325,USH1G;56113,USH2A;66151,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,0
"Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (@VARIANT$) and TNNT2 (Asn83His), both sarcomeric genes. Here we reported heterozygous variants in genes that play roles in two different cardiomyocyte components; MYH7:part of the sarcomere, and LAMA4:part of the ECM/signalling component. To our knowledge, this is the first description of digenic mutations in @GENE$ and @GENE$. The mutations were inherited from the parents, the mother carrying a MYH7 mutation and with mild DCM, and a father carrying the LAMA4 variation but with a normal heart at age 29. It is unclear whether the latter mutation can cause DCM on its own or if it plays a modifier role in the disease, however, long-term follow-up might clarify the association. Given the severe DCM phenotype in the proband at age 10 months and the presence of two different mutated genes in two different cardiomyocyte components, we believe that the LAMA4 p.Asp1309Asn variation found here may cause a mild defect in LAMA4 function that only manifests in combination with the digenic inheritance of the MYH7 @VARIANT$ mutation.",6359299,MYH7;68044,LAMA4;37604,Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"  Digenic inheritances of @GENE$/MITF and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus.",4998745,GJB2;2975,GJB6;4936,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2). While @GENE$ blocks VEGF/VEGFR2 signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,RASA1;2168,TIMP3;36322,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0
"  In patient AVM427, the de novo heterozygous missense variant c.3442G>T (@VARIANT$) was identified in @GENE$ (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating BMP signalling. In addition to Smad1-mediated BMP signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-Smad4 complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, c.1891G>T (p.Glu631Ter), in EGFR (table 1). Oncogenic @GENE$ stimulates angiogenesis via the VEGF pathway. As a truncated germline EGFR variant has not been reported in humans, @VARIANT$ (p.Glu631Ter) in patient AVM312 was classified as likely pathogenic and EGFR as a candidate gene due to the vital role of EGFR in EGF and VEGF signalling.",6161649,ZFYVE16;8826,EGFR;74545,p.Asp1148Tyr;tmVar:p|SUB|D|1148|Y;HGVS:p.D1148Y;VariantGroup:3;CorrespondingGene:9765,c.1891G>T;tmVar:c|SUB|G|1891|T;HGVS:c.1891G>T;VariantGroup:8;RS#:909905659,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"This indicates that neither p.R143W in GJB2 nor @VARIANT$ in WFS1 contributed to SNHL in SH60-136 and that p.R143W in GJB2 was an incidentally detected variant in this subject. GJB2 = gap junction protein beta 2, SNHL = sensorineural hearing loss, @GENE$ = wolfram syndrome 1.             Single Heterozygous GJB2 Mutant Allele Possibly Contributing to Deafness via Digenic Inheritance: Double Heterozygosity with Additional Mutation in Other Deafness Genes (Group II) Interestingly, two subjects (SH107-225 and SH175-389) showed double heterozygosity for a GJB2 mutation and another likely pathogenic mutation in another deafness gene. We detected a de novo Microphthalmia-associated transcription factor (MITF) (NM_000248) variant, @VARIANT$, in one of the c.235delC carriers (SH107-225) (Figure 4A). She inherited c.235delC of GJB2 from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). The p.R341 residue of @GENE$ is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C).",4998745,WFS1;4380,MITF;4892,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; rs7673715) @VARIANT$; p.N409S and @GENE$ (MIM 600509; NM_000352.4; rs151344623) @VARIANT$ mutations.,5505202,GBA;68040,ABCC8;68048,c.1226A>G;tmVar:c|SUB|A|1226|G;HGVS:c.1226A>G;VariantGroup:7;CorrespondingGene:2629;RS#:76763715;CA#:116767,c.3989-9G>A;tmVar:c|SUB|G|3989-9|A;HGVS:c.3989-9G>A;VariantGroup:4;CorrespondingGene:6833;RS#:151344623;CA#:233276,1
   Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the GCK gene and in exon 4 (@VARIANT$; p.Pro291Arg) of the @GENE$ gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the HNF1A variant was present in the mother (Figure 1B).,8306687,HNF1A;459,GCK;55440,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,TRPV4;11003,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, @VARIANT$, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The LRP6 c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS. It was predicted to be ""possibly damaging"", with a PolyPhen-2 score of 0.767. The WNT10A mutation (c.499G>C, rs148714379), while being rare (MAF = 0.0003), was categorized as a benign variant (PolyPhen-2 score = 0.087). Segregation analysis showed that the father carried the two @GENE$ variants, while the mother and the younger sister were both heterozygotes for the WNT10A mutation.",8621929,WNT10A;22525,LRP6;1747,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and @VARIANT$ (p.Ser334Thr) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, R165W, F191L, and A197S in @GENE$ as well as @VARIANT$, S198F and @VARIANT$ in @GENE$, have been reported previously in patients with hearing impairment.",2737700,Cx26;2975,Cx32;137,F193C;tmVar:p|SUB|F|193|C;HGVS:p.F193C;VariantGroup:15;CorrespondingGene:2706,G199R;tmVar:p|SUB|G|199|R;HGVS:p.G199R;VariantGroup:17;CorrespondingGene:2705,0
"Additionally, I: 1 and II: 2 carried with the heterozygous for @GENE$ @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of @GENE$ @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b).",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, p.Tyr27His), MBD5 (NM_018328.4, @VARIANT$, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (@VARIANT$), @GENE$ (rs143445685), CAPN3 (rs138172448), and DES (rs144901249) genes. We hypothesized that the inheritance pattern could follow a digenic pattern of inheritance. Screening for these polymorphisms in an unaffected sister revealed the presence of all these same variants except for that in the CAPN3 gene. All variants were studied to determine their frequency and if they had been previously reported as mutations. They were also subjected to protein modeling programs, including SIFT, PolyPhen, and MutationTaster. This analysis indicated that the CAPN3 variant c.1663G>A (rs138172448), which results in a p.Val555Ile change, and the @GENE$ gene variant c.656C>T (@VARIANT$), which results in a p.Thr219Ile change, are both predicted to be damaging.",6180278,RYR1;68069,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, @VARIANT$, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"This phenotypic incomplete penetrance might be modified by @GENE$-@VARIANT$ variant and sex. As shown in Table 3, all male individuals carrying the @GENE$-@VARIANT$ mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant SCN5A-R1193Q showed the ERS phenotypes.",5426766,SCN5A;22738,CACNA1C;55484,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"We have identified a non-consanguineous family, who carry the C104R (@VARIANT$) mutation of the Transmembrane Activator Calcium-modulator and cyclophilin ligand Interactor (TACI, TNFRSF13B) gene. Variants in @GENE$/TACI are identified in up to 10% of CVID patients, and are associated with, but not solely causative of CVID. The proband is heterozygous for the TNFRSF13B/TACI C104R mutation and meets the Ameratunga et al. diagnostic criteria for CVID and the American College of Rheumatology criteria for systemic lupus erythematosus (SLE). Her son has type 1 diabetes, arthritis, reduced IgG levels and IgA deficiency, but has not inherited the TNFRSF13B/TACI mutation. Her brother, homozygous for the TNFRSF13B/TACI mutation, is in good health despite profound hypogammaglobulinemia and mild cytopenias. We hypothesised that a second unidentified mutation contributed to the symptomatic phenotype of the proband and her son. Whole-exome sequencing of the family revealed a de novo nonsense mutation (@VARIANT$) in the Transcription Factor 3 (@GENE$) gene encoding the E2A transcription factors, present only in the proband and her son.",5671988,TNFRSF13B;49320,TCF3;2408,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and p.(H395N); PITX2: @VARIANT$). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,1
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare @GENE$ missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PTK7;43672,CELSR2;1078,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The cells were transfected with cDNAs of encoding myc-pendrin diease forms with that of @GENE$, and the non-permeable cells were stained with an anti-myc antibody. While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, Q446R, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of @GENE$ (Fig. 5a) but partially restored membrane localization of myc-pendrin @VARIANT$, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,EphA2;20929,pendrin;20132,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Apart from the repeat expansion, a rare missense variant of uncertain significance (@VARIANT$) was also detected in the C9orf72 gene. According to the NGS results, the most frequently mutated genes were NEK1 (6/107, 5.6%), NEFH, SQSTM1 (4/107, 3.7%), KIF5A, @GENE$ (3/107, 2.8%), ALS2, CCNF, FUS, @GENE$, TBK1, and UBQLN2 (2/107, 1.9%). Furthermore, potentially relevant variants were found in the GRN and SIGMAR1 genes in single patients ( Table 2 ). Because of the relatively high prevalence of the NEK1 R261H variant in our patient cohort (5/107), we further evaluated 186 additional healthy controls (total 370) for this variant. @VARIANT$ was identified in 5/107 (4.67%) patients and 4/370 (1.08%) controls, showing an enrichment in patients (MAF: 0.0234 vs 0.0054; p = 0.0162).",6707335,SPG11;41614,MATR3;7830,R431Q;tmVar:p|SUB|R|431|Q;HGVS:p.R431Q;VariantGroup:19;CorrespondingGene:203228;RS#:753335393;CA#:5017643,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"This mutation changes codon 554 from arginine to a stop codon (c.1160C>T; @VARIANT$) and has been previously reported. The mother did not carry this luteinizing hormone/choriogonadotropin receptor (LHCGR) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, @GENE$, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described @VARIANT$ mutant. By contrast, GATA4 variants Trp228Cys and Pro226Leu activated the @GENE$ promoter similar to wt.",5893726,SRY;48168,CYP17;73875,p.Arg554Stop;tmVar:p|SUB|R|554|X;HGVS:p.R554X;VariantGroup:1;CorrespondingGene:3973;RS#:368991748,Gly221Arg;tmVar:p|SUB|G|221|R;HGVS:p.G221R;VariantGroup:4;CorrespondingGene:2626;RS#:398122402(Expired),0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin @VARIANT$ and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that @GENE$ could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane.",7067772,EphA2;20929,pendrin;20132,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
"The @GENE$ variant p.R450H was a recurrent inactivating mutation and @VARIANT$ and p.K618 were novel. p.C176R is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and @VARIANT$ and p.K618* are located in the cytoplasmic loops (Fig. S3C). Patients with GIS had a higher tendency to be affected with mutations than patients with TD [25/32 (78%) vs. 6/11 (54%), Fig. 2]. Variants in TG, TSHR, DUOXA2, SLC5A5 and PROP1 genes were found exclusively in patients with GIS, and 1 variant in @GENE$ was found in patients with TD.",7248516,TSHR;315,TRHR;20707,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,p.R528S;tmVar:p|SUB|R|528|S;HGVS:p.R528S;VariantGroup:25;CorrespondingGene:7253;RS#:765367813,0
"Therefore, in this study, SCN5A @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of @GENE$ @VARIANT$ and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and @GENE$ p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"TG mutations were the second most prevalent genetic alterations in DH: five different heterozygous variants were found in 5/21 patients (23.8%), and these often cooccurred with @GENE$ or DUOXA2 mutations. DUOX2 and TG mutation locations varied in the corresponding proteins (Figure 2). Additionally, three DUOXA2 variants were found in 3/21 patients (14%), and a known heterozygous variant in @GENE$ was found in one patient. No mutations in SLC5A5, TPO, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: @VARIANT$ (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,DUOX2;9689,SLC26A4;20132,c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"(D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB3;7338,GJB2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"GJB2 Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected @GENE$ Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, @VARIANT$ (c.100C>T) (rs121908073), and a novel variant, p.W482R of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R34X;tmVar:p|SUB|R|34|X;HGVS:p.R34X;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002,1
"(A) In addition to @VARIANT$ in @GENE$, the de novo variant of @GENE$, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates.",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Protein structure analysis We performed protein structure analysis on the two WNT10A mutations (p.R171C and @VARIANT$) and two novel @GENE$ mutations (@VARIANT$ and p.I312M) that were identified in this study. For @GENE$, the conservation of residues in sequences was determined to predict the influence of the two mutations.",3842385,EDA;1896,WNT10A;22525,p.G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"The @GENE$ and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,SETDB1;32157,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Moller et al. reported an index case with digenic variants in MYH7 (L1038P) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and @GENE$ (@VARIANT$), both sarcomeric genes.",6359299,MYBPC3;215,TNNT2;68050,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The @GENE$ @VARIANT$ mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,alsin;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ p.M170I and TAF15 @VARIANT$ with SETX p.I2547T and SETX p.T14I).",4293318,DCTN1;3011,VAPB;36163,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with @GENE$ p.M170I and TAF15 @VARIANT$ with SETX p.I2547T and SETX p.T14I).,4293318,ANG;74385,VAPB;36163,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, @VARIANT$, was identified in patient #3. @GENE$, @GENE$ and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS1;11641,BBS2;12122,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and @GENE$ @VARIANT$), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR2;1078,FZD6;2617,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"Earlier studies detected @VARIANT$ in 1.8% of ALS patients and 0.66% of controls with minor allele frequencies 0.009 and 0.0033, respectively. Based on these results, we assume that the NEK1 R261H variant is more frequent in the Hungarian population (both in patients and controls) than in other populations, although further large cohort studies are needed to confirm this conclusion. This study provides additional evidence that NEK1 missense variants may contribute to the development of sALS.    Missense variants in the @GENE$ gene were detected in four patients: the T338I variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene.",6707335,NEFH;40755,GRN;1577,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The @VARIANT$ and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the E389Q and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,0
"Moderate iodine deficiency in association with double heterozygosity for @GENE$ and DUOX2 mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous @GENE$ nonsense mutation (c.1300 C>T, @VARIANT$).",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 3;7338,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"          Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the @GENE$ and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (c.791G A) resulting in substitution of a valine by methionine at position 255 (p.V255M) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b). This mutation was not present in 100 control alleles by restriction enzyme digestion and/or by direct nucleotide sequencing (Fig. 3c). Secondly, a single nucleotide substitution (@VARIANT$ T) resulting in substitution of a @VARIANT$ (p.S300F) was detected (Fig. 3d).",2900916,GGCX;639,VKORC1;11416,c.927C;tmVar:c|Allele|C|927;VariantGroup:3;CorrespondingGene:368;RS#:528603039,serine by phenylalanine in position 300;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0
"A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. The authors raised the possibility of a digenic myopathy, which up to date has not been proven.     Herein, we describe the clinical and pathological phenotype of three unrelated probands harboring the combined heterozygous @GENE$ and @GENE$ variants in the setting of MRV or myofibrillar pathology, providing evidence that co-occurrence of these variants are associated with late-onset myopathy.",5868303,TIA1;20692,SQSTM1;31202,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"This phenotypic incomplete penetrance might be modified by @GENE$-R1193Q variant and sex. As shown in Table 3, all male individuals carrying the @GENE$-@VARIANT$ mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant SCN5A-@VARIANT$ showed the ERS phenotypes.",5426766,SCN5A;22738,CACNA1C;55484,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Mutations in NRXN1 and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (@VARIANT$) and @GENE$ (@VARIANT$), both sarcomeric genes. Here we reported heterozygous variants in genes that play roles in two different cardiomyocyte components; MYH7:part of the sarcomere, and LAMA4:part of the ECM/signalling component. To our knowledge, this is the first description of digenic mutations in MYH7 and LAMA4. The mutations were inherited from the parents, the mother carrying a MYH7 mutation and with mild DCM, and a father carrying the @GENE$ variation but with a normal heart at age 29.",6359299,TNNT2;68050,LAMA4;37604,Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, @VARIANT$) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,p.Met1445Val;tmVar:p|SUB|M|1445|V;HGVS:p.M1445V;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,GJB6;4936,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR2;1078,FAT4;14377,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"One patient had a novel de novo variant of @GENE$ (c.1524delA, @VARIANT$) and a hot spot variant of @GENE$ (c.533G > C, @VARIANT$) simultaneously.",8796337,KAl1;55445,PROKR2;16368,p. Ser509fs;tmVar:p|FS|S|509||;HGVS:p.S509fsX;VariantGroup:19;CorrespondingGene:3730,p. Trp178Ser;tmVar:p|SUB|W|178|S;HGVS:p.W178S;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917,1
"The TIA1 variant is designated as @VARIANT$ and reported at allele frequencies of 0.0071 in ExAC, 0.0016 in TGP, and 0.0068 in GO-ESP (accessed January 23, 2018). We examined the genotype data in the TGP to determine whether these variants coincide in controls. None of 2,504 self-declared healthy individuals in TGP has both @GENE$, c.1070A > G (p.Asn357Ser) and @GENE$, c.1175C > T (@VARIANT$).",5868303,TIA1;20692,SQSTM1;31202,rs116621885;tmVar:rs116621885;VariantGroup:5;CorrespondingGene:7072;RS#:116621885,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"The loss-of-function variation in @GENE$ or @GENE$ (e.g., CACNA1C-@VARIANT$), which produces inadequate inward hybrid currents, is responsible for the pathopoiesis of ERS. Thus, from the mechanistic point of view, INa and ICa-L show a synergistic effect on the repolarization as two ingredients of the inward currents. In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental CACNA1C-Q1916R mutation might be partly compensated by the persistent inward tail INa produced by the SCN5A-R1193Q channel. That may be how SCN5A-@VARIANT$ plays a protective role against the detrimental phenotype induced by the CACNA1C-Q1916R mutation.",5426766,SCN5A;22738,CACNA1C;55484,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (c.6657T>C), @GENE$ (c.46C>G; @VARIANT$) and USH2A (@VARIANT$).",3125325,MYO7A;219,USH1G;56113,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"@VARIANT$ lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this G-protein coupled receptor, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in CHD7, FGF8, FGFR1, PROK2, @GENE$, TAC3, KAL1, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that @GENE$ is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;@VARIANT$ from NP_056352).",3888818,PROKR2;16368,NELF;10648,Trp275;tmVar:p|Allele|W|275;VariantGroup:1;CorrespondingGene:6870;RS#:144292455,p.Thr478Ala;tmVar:p|SUB|T|478|A;HGVS:p.T478A;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (rs144651558), @GENE$ (rs143445685), CAPN3 (@VARIANT$), and DES (@VARIANT$) genes.",6180278,COL6A3;37917,RYR1;68069,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, @VARIANT$, p.S82T, p. A85P, @VARIANT$, p.F112S, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.P79T;tmVar:p|SUB|P|79|T;HGVS:p.P79T;VariantGroup:108;CorrespondingGene:6012,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,0
" @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene. Variants in the @GENE$ gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia.",6707335,MATR3;7830,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, rs2302686), 0.0007 (LRP6 @VARIANT$, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,REEP4;11888,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"The female CACNA1C-@VARIANT$ mutation carriers with @GENE$-@VARIANT$ variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the @GENE$-Q1916R mutation (IV-4) showed the ER ECG pattern.",5426766,SCN5A;22738,CACNA1C;55484,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"As negative control, no interaction was detected between the GFP tag and HA-@GENE$ proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2).",5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"(D) The @GENE$ mutation c.457C>T and WNT10A mutation c.637G>A were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis. (E) The EDA mutation c.466C>T and @GENE$ mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in EDA and c.511C>T in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant p.A2282T and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that @GENE$ may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ FLNB and p.Y437F OFD1 (figure 3D).",7279190,TTC26;11786,FLNB;37480,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,0
"While tagged versions of EphA2 G355R and EphA2 @VARIANT$ were effectively precipitated with Fc-fusion ephrin-A1 compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down @GENE$ G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 G355R and EphA2 T511M with pendrin induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as @VARIANT$, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum. Low temperature incubation and salicylate treatment of cultured cells, which are thought to help with protein-folding processes, rescues the membrane localization of H723R. On the other hand, mis-localization of pendrin A372V from the plasma membrane is not restored by these treatments, suggesting these mutations may affect @GENE$ trafficking from the Golgi to the plasma membrane but not protein-folding.",7067772,EphA2;20929,pendrin;20132,T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0
"In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the E389Q and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The LRP6 @VARIANT$ mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,LRP6;1747,WNT10A;22525,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"The side chains of R/@VARIANT$ are shown as sticks, and the other residues are shown as lines. (D) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.R2003H) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$).",7279190,FLNB;37480,OFD1;2677,H2003;tmVar:H2003;VariantGroup:31;CorrespondingGene:2317,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,1
"Mutation name is based on the full-length @GENE$ (NM_002960) and @GENE$ (NM_001024210) transcripts.    Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, @VARIANT$ in SETDB1 and @VARIANT$ in S100A3, and one novel variant in S100A13, were identified.",6637284,S100A3;2223,S100A13;7523,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"Mutations in @GENE$ and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (c.229C>T; @VARIANT$) and d) the @VARIANT$ (p.I80Gfs*13) in @GENE$. Mutation name is based on the full-length @GENE$ (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A13;7523,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (@VARIANT$ of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Nevertheless, when it occurs with a defect in @GENE$, which functions in the same pathway, a combination of deficiencies results in a severe disease phenotype. This phenomenon of ""synthetic lethality"" has long been described in genetics and thought to be implicated in the molecular pathogenesis of digenic inheritance in genetic disorders. In this study, we also showed that a second @GENE$ variant in trans might potentially modify the expressivity of a primary ""driver"" mutation. The proband of Family 3 was a compound heterozygote of p.(Ala754Pro) and p.(@VARIANT$) mutations and had fourteen missing teeth, while his father, who carried the p.(@VARIANT$) mutation, exhibited only two.",8621929,WNT10A;22525,LRP6;1747,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"(b) The changed site of SCN5A gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant DISCUSSION In our study, the proband with overlapped phenotypes of young early-onset LQTS and sinoatrial node dysfunction was first demonstrated to carry with the digenic heterozygous and pathogenic mutations of @GENE$ @VARIANT$ and SCN5A p.R1865H. KCNH2 p.307_308del induced a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized, which thus mainly caused LQTS. The @GENE$ @VARIANT$ slightly increased the molecular weight and aliphatic index, but reduced the instability index of Nav1.5 protein property, which potentially induced subsequent sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"  We report digenic variants in @GENE$and @GENE$ in spina bifida and anencephaly cases, and CELSR1and DVL3 in anencephaly cases, involving 4 combinatorial variants that were uniquely present in cases but absent in the 1000G database. All of these variants had a minor allele frequency < 0.01 in the ExAC population database and the 1000 genome data of Han Chinese population in Beijing, save for the novel variant SCRIB c.1853A > G (@VARIANT$), which was not found in either the dbSNP database or 1000 genome data or ExAC database or among parental samples of the NTD cases. All of these rare variants were predicted to be detrimental in silico. During amino acid conservation analysis, over half of the variants were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish, while the others involved less conserved nucleotides. Location analysis of the missense changes showed that the p.R769W and @VARIANT$ were mapped to the cadherin repeats (CA domain) of CELSR1.",5966321,CELSR1;7665,SCRIB;44228,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 @VARIANT$ (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. @GENE$ gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,SCN5A;22738,KCNH2;201,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"@GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2).",6161649,SCUBE2;36383,RASA1;2168,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0
"The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in @GENE$, p.(Arg872Gly).",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"For example, two variants in proband P15, @VARIANT$ in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother.",8152424,DCAF17;65979,DMXL2;41022,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for REEP4 @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates                @GENE$ missense variant A TOR2A nonsynonymous SNV (c.568C>T [NM_130459.3], @VARIANT$ [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,BSP+;3644,TOR2A;25260,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,ATP2A3;69131,MYOD1;7857,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"Quantification of cells with dilated endoplasmic reticulum (ER) and COPII vesicles associated with Golgi by transmission electron microscopy Genotype of cell line Cells with dilated ER (%) Cells with Golgi-associated vesicles (%) Wt (N = 414) 2 (0.5) 309 (75) SEC23Ac.1200G>C/+ (N = 83) 83 (100***) 9 (11***) SEC23Ac.1200G>C/+ MAN1B1@VARIANT$/+ (N = 190) 190 (100***) 3 (1.6***) SEC23Ac.@VARIANT$/c.1200G>C; MAN1B1c.1000C>T/c.1000C>T (N = 328) 328 (100***) 2 (0.6***)  Increased Intracellular and Secreted Pro-COL1A1 in Fibroblasts with Homozygous Mutations in Both @GENE$ and @GENE$ in the Presence of l-Ascorbic Acid SEC23A is required for normal transport of pro-COL1A1, a major extracellular matrix component of bone.",4853519,SEC23A;4642,MAN1B1;5230,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between @GENE$ and MYOD1 has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2).",7549550,RIPPLY1;138181,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Novel Missense Mutation in the @GENE$ Gene in a Patient with Early Onset Ulcerative Colitis: Causal or Chance Association? Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn's disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A > G @VARIANT$) and two already described missense variants in the @GENE$ gene (S159G and @VARIANT$).",3975370,NOD2;11156,IL10RA;1196,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (c.6657T>C), USH1G (@VARIANT$; p.L16V) and @GENE$ (@VARIANT$).",3125325,MYO7A;219,USH2A;66151,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and @GENE$ R80Q. Both mutations are novel and whilst a different mutation, R80W, has been reported in HNF4A, further evidence to support the pathogenicity of E508K is lacking. The siblings we describe with the HNF1A P291fsinsC and HNF4A @VARIANT$ mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic.",4090307,HNF1A;459,HNF4A;395,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of @GENE$ were detected.,3842385,EDA;1896,WNT10A;22525,p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"By contrast, GATA4 variants @VARIANT$ and @VARIANT$ activated the CYP17 promoter similar to wt. Transcriptional activity of @GENE$ variants on the @GENE$ promoter.",5893726,GATA4;1551,CYP17A1;73875,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:@VARIANT$; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.",4470809,TBK1;22742,OPTN;11085,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The two mutations (@VARIANT$ and @VARIANT$) affect amino acid residues located in the motor head of myosin VIIa, and have previously been reported in USH1 patients. They may preserve a residual activity of the protein, thus causing less severe hearing, balance and visual impairments. Alternatively, one of these mutations or both might be deleterious for the myosin VIIa activity associated with the ankle-link protein complex that underlies the USH2 phenotype, but not with the transient hair bundle lateral-link and tip-link molecular complexes that are involved in USH1 pathogenesis. These phenotype/genotype discrepancies further argue in favor of a comprehensive mutation screening procedure that includes genes seemingly inconsistent with the clinical classification of USH currently in use. Notably, our study has revealed one case of likely oligogenic inheritance for USH1, involving MYO7A and USH1G, and possibly USH2A. Three cases of digenic inheritance of USH1 have been reported so far, all caused by mutations in @GENE$ and @GENE$, in agreement with the contribution of cadherin-23 and protocadherin-15 to the hair bundle transient lateral links and tip-links.",3125325,CDH23;11142,PCDH15;23401,p.A457V;tmVar:p|SUB|A|457|V;HGVS:p.A457V;VariantGroup:19;CorrespondingGene:4647;RS#:111033286;CA#:278624,p. K269del;tmVar:p|DEL|269|K;HGVS:p.269delK;VariantGroup:249;CorrespondingGene:26820,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,DFNB1;2975,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Neither the @VARIANT$ nor the @VARIANT$ variant has been reported as a mutation of a compound heterozygote in patients diagnosed with a myopathy secondary to mutations in either the DES or CAPN genes. Discussion The patient's history, clinical examination, EMG testing, muscle biopsy results, and the lack of response to any therapy suggest that he does not have an inflammatory myopathy but rather a genetic disorder. Mutations in CAPN3 and DES genes result in LGMD inherited in an autosomal recessive pattern. Homozygous or compound heterozygous mutations in the CAPN3 and DES genes cause LGMD 2A and LGMD 2R, respectively. However, the results of the genetic analysis of the most common forms of muscular dystrophy did not reveal mutations that could account for his condition by considering conventional patterns of autosomal recessive inheritance. This patient carries 2 damaging variants in the @GENE$ and @GENE$ genes.",6180278,DES;56469,CAPN3;52,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes.     ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90.",3842385,EDA;1896,WNT10A;22525,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,0
"However, none of these signs were evident from metabolic work of the patient with @GENE$ L718F, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 @VARIANT$ and @GENE$ @VARIANT$ variants remain unknown.",6072915,PHKA1;1981,NDUFS8;1867,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0
"Circles, female; squares, male; gray, @GENE$/TACI C104R mutation; blue TCF3 T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and C104R (c.310T>C) mutation of TACI gene in the proband II.2.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"@VARIANT$ carriers required different surgical procedures for correct IOP control (Table 2). This nucleotide substitution also mapped at FOXC2-@GENE$ intron 1 (@VARIANT$) and the regulatory feature (promoter) (Fig 1C), and it was inferred to produce a low functional effect on FOXC2 and a modifier outcome on both @GENE$ and the overlapping promoter.",6338360,AS1;736,FOXC2-AS1;103752587;2303;5729,p.(S36S);tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260,n.145+174G>A;tmVar:n|SUB|G|145_174|A;VariantGroup:14;CorrespondingGene:5729,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in MYO7A and @VARIANT$ in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in @GENE$. Another variation, 158-1G>A in intron 3 of PCDH15, was derived from the proband and his father.",3949687,PCDH15;23401,MYO7A;219,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,0
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for connexin 26 (@GENE$) and connexin 31 (@GENE$) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in @GENE$ to block its activity in BMP/TGF-beta signalling.",6161649,MAP4K4;7442,SMAD1;21196,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"21  Additional gene reportedly linked to tumorigenesis include @GENE$, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, @VARIANT$) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: @VARIANT$, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, @GENE$ variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis.",7689793,RYR3;68151,TRIP6;37757,p.Asn2604Lys;tmVar:p|SUB|N|2604|K;HGVS:p.N2604K;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,CELSR1;7665,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Her in vitro IgG production is substantially lower than that of her TNFRSF13B/TACI C104R heterozygous brother (II.3) and her @GENE$ @VARIANT$ heterozygous son (III.1), who individually bear each mutation. While clear defects in B-cell development, isotype switching and differentiation into ASCs were observed in both individuals (II.2 and III.1) carrying the mutant TCF3 allele, the additional effect of the @VARIANT$ @GENE$ mutation in the proband (II.2) resulted in a more severe B lymphocyte cellular phenotype, consistent with epistasis.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The side chains of R/@VARIANT$ and A/T2282 are shown as sticks, and the other residues are shown as lines. (D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.R566L, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (p.R297C, @VARIANT$).",7279190,FLNB;37480,TTC26;11786,L566;tmVar:p|Allele|L|566;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,0
"(A) In addition to @VARIANT$ in @GENE$, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus. (C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates.",4998745,GJB2;2975,GJB6;4936,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (@VARIANT$)::CYP1B1 (@VARIANT$), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of TEK to respond to ligand stimulation, indicating perturbed @GENE$ signaling. Overall, our data suggest that interaction of TEK and @GENE$ contributes to PCG pathogenesis and argue that TEK-CYP1B1 may perform overlapping as well as distinct functions in manifesting the disease etiology.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"He also had a KAL1 deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, @GENE$, @GENE$, GNRHR, GNRH1, or KISS1R.",3888818,TAC3;7560,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"This nucleotide substitution also mapped at @GENE$-AS1 intron 1 (@VARIANT$) and the regulatory feature (promoter) (Fig 1C), and it was inferred to produce a low functional effect on FOXC2 and a modifier outcome on both @GENE$ and the overlapping promoter. The nucleotide change @VARIANT$ was located in the 3'UTR of the gene (Fig 1A) and was identified in one patient diagnosed at the age of two and a half months, who required several trabeculectomies to correct IOP (Table 2).",6338360,FOXC2;21091,FOXC2-AS1;103752587;2303;5729,n.145+174G>A;tmVar:n|SUB|G|145_174|A;VariantGroup:14;CorrespondingGene:5729,c.*38T>G;tmVar:c|SUB|T|*38|G;HGVS:c.*38T>G;VariantGroup:6;CorrespondingGene:103752587;RS#:199552394,0
"The functional impact of the second PITX2 amino acid substitution, @VARIANT$, could not be functionally evaluated due to DNA cloning difficulties. In fact, the two @GENE$ amino acid changes were found to be hypomorphic whereas the @GENE$ amino acid substitution (@VARIANT$) behaved experimentally as a hypermorphic variant.",6338360,FOXC2;21091,PITX2;55454,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"The @GENE$ and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. Allele frequency for rs138355706 within the population was calculated from exome sequencing of 2000 individuals and was found to be 0.1% (unpublished data from the Saudi Human Genome Project; www.saudigenomeprogram.org). Furthermore, 500 ethnically matched normal controls were genotyped for this change by re-sequencing of S100A3. Three of these individuals were heterozygous, but none was homozygous for @VARIANT$. Sequencing of the S100A3 intronic and 5'-flanking sequences was performed in the affected patients and no other variants were identified (data not shown).",6637284,ISG20L2;12814,SETDB1;32157,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"The mutations of @GENE$ @VARIANT$ and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous @GENE$ p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (@GENE$)@VARIANT$, and @GENE$ @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,DCC;21081,FGFR1;69065,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,1
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The four other variants (CELSR1 @VARIANT$, @GENE$ p.R1057C and @GENE$ @VARIANT$) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,CELSR1;7665,SCRIB;44228,p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the @GENE$ and @GENE$ proteins lead us to hypothesize that digenic variants in NRXN1 and NRXN2 contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), @GENE$ (@VARIANT$; p.L16V) and USH2A (c.9921T>G).",3125325,MYO7A;219,USH1G;56113,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,1
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The @VARIANT$ (@VARIANT$) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in @GENE$ was also identified. Although no direct interaction between @GENE$ and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).",7549550,MYOD1;7857,RIPPLY1;138181,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"  To gain further insight into the role of EphA2 on @GENE$ regulation, pendrin @VARIANT$, L445W, Q446R or G672E was co-overexpressed with EphA2. The cells were transfected with cDNAs of encoding myc-pendrin diease forms with that of EphA2, and the non-permeable cells were stained with an anti-myc antibody. While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, Q446R, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of @GENE$ did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,pendrin;20132,EphA2;20929,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and @GENE$ c.3323G > A (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. Location analysis of missense changes showed that @VARIANT$ was located very close to the fourth PDZ domain (1109-1192) of SCRIB.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be DFNB7/11, @GENE$, and @GENE$, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES.",4998745,DFNB3;56504,DFNB16;15401,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and @GENE$ (c.9921T>G).",3125325,MYO7A;219,USH2A;66151,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"The two mutations (@VARIANT$ and @VARIANT$) affect amino acid residues located in the motor head of @GENE$, and have previously been reported in USH1 patients. They may preserve a residual activity of the protein, thus causing less severe hearing, balance and visual impairments. Alternatively, one of these mutations or both might be deleterious for the myosin VIIa activity associated with the ankle-link protein complex that underlies the USH2 phenotype, but not with the transient hair bundle lateral-link and tip-link molecular complexes that are involved in USH1 pathogenesis. These phenotype/genotype discrepancies further argue in favor of a comprehensive mutation screening procedure that includes genes seemingly inconsistent with the clinical classification of USH currently in use. Notably, our study has revealed one case of likely oligogenic inheritance for USH1, involving MYO7A and USH1G, and possibly USH2A. Three cases of digenic inheritance of USH1 have been reported so far, all caused by mutations in @GENE$ and PCDH15, in agreement with the contribution of cadherin-23 and protocadherin-15 to the hair bundle transient lateral links and tip-links.",3125325,myosin VIIa;219,CDH23;11142,p.A457V;tmVar:p|SUB|A|457|V;HGVS:p.A457V;VariantGroup:19;CorrespondingGene:4647;RS#:111033286;CA#:278624,p. K269del;tmVar:p|DEL|269|K;HGVS:p.269delK;VariantGroup:249;CorrespondingGene:26820,0
"Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (@VARIANT$) and TNNT2 (@VARIANT$), both sarcomeric genes. Here we reported heterozygous variants in genes that play roles in two different cardiomyocyte components; MYH7:part of the sarcomere, and LAMA4:part of the ECM/signalling component. To our knowledge, this is the first description of digenic mutations in @GENE$ and @GENE$. The mutations were inherited from the parents, the mother carrying a MYH7 mutation and with mild DCM, and a father carrying the LAMA4 variation but with a normal heart at age 29.",6359299,MYH7;68044,LAMA4;37604,Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0
"However, one of the patients heterozygous for the @VARIANT$ mutation in @GENE$ (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in @GENE$ exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,PROKR2;16368,KAL1;55445,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,1
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in @GENE$ (p.K268R), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, @GENE$ and USH2A were not found in 666 control alleles.",3125325,MYO7A;219,USH1G;56113,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,0
"The latter individuals were also carriers of the ABCC6 nonsense mutation @VARIANT$. It should be noted that the mother and her twin sister were heterozygous for one of the GGCX missense mutation @VARIANT$ and one ABCC6 nonsense mutation p.R1141X, suggesting digenic inheritance of their cutaneous findings. The occurrence of digenic inheritance, although rare, is well established (see e.g.,). The chance of a combination of mutations in the @GENE$ and @GENE$ genes is difficult to calculate, since the precise carrier frequency of the mutations in these genes is not known.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"M2, CYP1B1: @VARIANT$. M3, @GENE$: p.(E173*). M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:@VARIANT$; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the @GENE$ missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for connexin 26 (Cx26) and @GENE$ (Cx31) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 @GENE$ heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,connexin 31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,KCNE2;71688,KCNH2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant @VARIANT$. The @GENE$ gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,DUSP6;55621,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"A rare variant in @GENE$, c.428C>T; @VARIANT$, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/@GENE$ (@VARIANT$; p.Met544Ile) pathogenic missense alteration was identified.",7696449,AMH;68060,FOG2;8008,p.Thr143Ile;tmVar:p|SUB|T|143|I;HGVS:p.T143I;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,c.1632G>A;tmVar:c|SUB|G|1632|A;HGVS:c.1632G>A;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the DYNC1H1 gene. Variants in the DYNC1H1 gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the @GENE$ gene in fALS and sALS patients, suggesting its role in ALS.",6707335,MATR3;7830,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT6;71688,KCNH2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, p. A85P, @VARIANT$, p.F112S, p.R127L, @VARIANT$, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,FOXC1;20373,PITX2;55454,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,p.G149D;tmVar:p|SUB|G|149|D;HGVS:p.G149D;VariantGroup:15;CorrespondingGene:1805;RS#:777651623,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"                                 Quantitation of epistatic interactions of @GENE$ and @GENE$ mutations showing a greater net effect than the sum of each individual mutation. Total Serum Ig, clinical score and TNFRSF13B/TACI @VARIANT$ and TCF3 @VARIANT$ genotype for each family member, as indicated.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T161fsX191;tmVar:p|FS|T|161||191;HGVS:p.T161fsX191;VariantGroup:5;CorrespondingGene:6929,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,DFNB1;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: @VARIANT$ and @VARIANT$; PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare FOXC2 and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"@VARIANT$ might affect the normal splicing of exons in the PROK2 gene, and the novel variant c.306G > C (p. Arg102Ser) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a PROK2 gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the PROKR2 gene were found in eight patients. c.337 T > C (p. Tyr113His) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. c.491G > A (p. Arg164Gln) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors. The hot spot variant c.533G > C (@VARIANT$) was found in six patients and located in the transmembrane domain of the protein, which could significantly reduce the release of ionized calcium and the signal activity.                             The @GENE$ gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the @GENE$/FGFR1 signalling pathway.",8796337,FGFR1;69065,FGF;8822;8822,c.223 - 4C > A;tmVar:c|SUB|C|223-4|A;HGVS:c.223-4C>A;VariantGroup:21;CorrespondingGene:60675,p. Trp178Ser;tmVar:p|SUB|W|178|S;HGVS:p.W178S;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917,0
"Interestingly, the FTLD-TDP patient carrying the OPTN deletion is case B, who also carries the TBK1 @VARIANT$ nonsense mutation, suggesting an oligogenic disease mechanism. Prompted by the idea of an oligogenic mechanism of disease we further looked at the presence of more frequent variants (MAF <0.1%) in individuals already harboring extremely rare variants in @GENE$ and TBK1 and noted that case A carrying the p.Gln235* nonsense variant in OPTN, is compound heterozygote for mutations in OPTN as it also carries the rare variant @VARIANT$ (NM_001008211.1:c.1442C>T) in OPTN (MAF=0.0116% in ESP - CADD_Phred score: 34). In order to evaluate the likelihood of OPTN and @GENE$ to harbor rare compound heterozygous variants or double mutations, we applied the same stringent filters that we used for our FTLD-TDP cases to our control dataset (155 Harvard PGP controls and 100 parents of intellectual disability patients).",4470809,OPTN;11085,TBK1;22742,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,p.Ala481Val;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"This analysis indicated that the CAPN3 variant @VARIANT$ (rs138172448), which results in a p.Val555Ile change, and the DES gene variant c.656C>T (rs144901249), which results in a @VARIANT$ change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the @GENE$ and @GENE$ genes, through digenic inheritance, are the cause of the myopathy in this patient.",6180278,CAPN3;52,DES;56469,c.1663G>A;tmVar:c|SUB|G|1663|A;HGVS:c.1663G>A;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,p.Thr219Ile;tmVar:p|SUB|T|219|I;HGVS:p.T219I;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,1
"While both @GENE$ variants, p.(@VARIANT$) and p.(Asn1075Ser), were inherited from her father, the @GENE$ mutation, @VARIANT$ was maternally derived.",8621929,LRP6;1747,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"He had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, KAL1, @GENE$, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) @GENE$ variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;@VARIANT$ from NP_056352). Since Thr478 was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease.",3888818,GNRHR;350,NELF;10648,p.Thr478Ala;tmVar:p|SUB|T|478|A;HGVS:p.T478A;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB2;2975,GJB6;4936,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"However, the two rare @GENE$ variants (Y25C and P106L) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein. Although the majority of FUS mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging.       In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel @VARIANT$ deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, @GENE$ is a causative gene of ALS-FTD. The NEK1 @VARIANT$ variant was also present in this patient.",6707335,FUS;2521,TBK1;22742,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,0
"On the other hand, mutant GFP-@GENE$ @VARIANT$ and R368H showed perturbed interaction with HA-@GENE$. The residues @VARIANT$, I148, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103;tmVar:p|Allele|E|103;VariantGroup:2;CorrespondingGene:7010;RS#:572527340,0
"Notably, the patients carrying the @VARIANT$ and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,0
"Despite the absence of IgG detected in the supernatants of these cultures, no defect was observed in the generation of isotype switched IgG+ cells in II.2 (carrying both TNFRSF13B/@GENE$ @VARIANT$ and @GENE$ @VARIANT$ mutations), compared to III.2, who has neither mutation.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,1
"                                    Tumor analysis MMR deficiency in tumor samples was assessed by microsatellite instability analysis and immunohistochemical detection of the four MMR proteins (MLH1, MSH2, @GENE$, and @GENE$). 11  KRAS codon 12/13 mutations were screened with Sanger sequencing. 12   Functional MMR assay In vitro MMR activity assay was performed as previously described. 13   RESULTS We performed germline whole-exome sequencing on three CRC patients diagnosed before 60 years of age (III-1, III-7, III-8, Figure 1A) and who belonged to a CRC family comprising of seven cancer patients divided over two generations. Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: c.3299C > T, @VARIANT$) and MUTYH (NM_001128425.1: c.536A > G, @VARIANT$) genes, while the other 20 genes could not be clearly linked to cancer predisposition.",7689793,MSH6;149,PMS2;133560,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,DCTN1;3011,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"The A194T substitution might cause conformational changes within the Cx31 molecule or affect the ability of @GENE$ to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the @GENE$ mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, @VARIANT$, F191L, and A197S in Cx26 as well as F193C, @VARIANT$ and G199R in Cx32, have been reported previously in patients with hearing impairment.",2737700,Cx31;7338,Cx26;2975,R165W;tmVar:p|SUB|R|165|W;HGVS:p.R165W;VariantGroup:5;CorrespondingGene:2706;RS#:376898963;CA#:180672,S198F;tmVar:p|SUB|S|198|F;HGVS:p.S198F;VariantGroup:14;CorrespondingGene:2705,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Another exonic variant in the @GENE$ gene (NM_013281), as well as two splice site variants in WDR11 (NM_018117) and @GENE$ (NM_015295) genes, was only present in the index case HH1 (Table 2). All these variants were frequent, with a MAF ranging from 0.2 to 0.6 according to the GnomAD database, except for the missense variant [@VARIANT$; p.(Arg935Trp)] in the CCDC141 gene (MAF = 0.06) (Supplementary Table 2). This variant was absent in the in-house control database. Despite being predicted as benign by Varsome, this variant [p.(Arg935Trp)] was involved in the second most important pathogenic combinations (15%; 13 genes) in HH1, after the PROKR2 gene variant [p.(@VARIANT$)].",8446458,FLRT3;8322,SMCHD1;23665,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,Pro290Ser;tmVar:p|SUB|P|290|S;HGVS:p.P290S;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"In fact, variant p.(@VARIANT$) has been found together with another variant in NOTCH3 (NM_000435.2:c.6532C>T:p.(@VARIANT$)), which means that further analysis must be performed to confirm the role of these changes. Only one patient has been found to have a VUS in CBLN2, but further analysis needs to be done to elucidate the possible role of this gene in PAH. In patients with PAH associated with CHD, we found ten variants in eight samples, three classified as pathogenic (two in BMPR2 in two siblings and one in TBX4) and six VUS in CPS1, ABCC8, SMAD5, SARS2, @GENE$, and @GENE$ (Table 3).",7650688,SMAD1;21196,NOTCH3;376,Glu1326Lys;tmVar:p|SUB|E|1326|K;HGVS:p.E1326K;VariantGroup:9;CorrespondingGene:6833;RS#:200563930;CA#:5902631,Pro2178Ser;tmVar:p|SUB|P|2178|S;HGVS:p.P2178S;VariantGroup:1;CorrespondingGene:4854;RS#:751951476;CA#:9262360,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in EHMT1 and c.353A > G (@VARIANT$) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (@GENE$ @VARIANT$ at a rate of 4.95 x 10-5, MFSD8 c. 353A > G at a rate of 8.24 x 10-6).",7463850,MFSD8;115814,EHMT1;11698,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0
"The MFE of @GENE$ @VARIANT$ mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.           RNA secondary structural prediction. (a, b) Compared with wild-type KCNH2, the structure of @GENE$ @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROK2;9268,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,alsin;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Moreover, expression of @GENE$ is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: @VARIANT$, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs.",6081235,MYH13;55780,NOS2;55473,c.2059C>T;tmVar:c|SUB|C|2059|T;HGVS:c.2059C>T;VariantGroup:11;RS#:200336122,p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126,0
"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (@VARIANT$ or @VARIANT$); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including @GENE$, @GENE$, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TPO;461,TG;2430,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; @VARIANT$, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,g.124339A>G;tmVar:g|SUB|A|124339|G;HGVS:g.124339A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"In Gata4ki mice with @VARIANT$ mutation interaction of Gata4 with cofactor Fog is abrogated, and consequently animals display anomalies of testis development. Moreover, GATA4 functionally interacts with NR5A1 in Sertoli cell cultures to positively regulate the expression of AMH, and therefore, it has been reported that mutations in @GENE$ may cause 46,XY DSD due to lack of interaction with GATA. No gonadal involvement is mostly detected in families with GATA4 mutations and isolated CHD, possibly because some of the variants retain some DNA-binding activity and exhibit different degrees of transcriptional activation on gonadal promoters and thus, remain able to synergize with NR5A1. In the present study, the p.Cys238Arg mutation was found in a patient with a complex CHD, genital ambiguity, and persistent Mullerian ducts, which led to female gender assignment. We propose that cysteine to arginine change in position 238 of GATA4 lacks activity to bind DNA reducing the transactivation of @GENE$ critically.  By contrast, variants @VARIANT$ and pTrp228Cys found in cases 2 and 3 did not affect CYP17 promoter activity.",5893726,NR5A1;3638,AMH;68060,p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463,p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0
"In Family F, the @GENE$/@VARIANT$ was inherited from the unaffected father and the A194T of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the @VARIANT$/GJB3, while the mother is heterozygous for the GJB2/299-300delAT (Fig. 1k).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT6;71688,LQT2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, @GENE$ and USH2A were not found in 666 control alleles.",3125325,CDH23;11142,USH1G;56113,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,DFNB1;2975,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"    A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
Shown is the single AA cysteine in frame @GENE$ deletion in the whey-acidic-protein domain (WAP) in B:although the annotation (@VARIANT$) was incorrect in our previous report. Also shown is the @GENE$ truncation mutation @VARIANT$ within a cytoplasmic domain between the 5th and 6th transmembrane domains in C).,3888818,KAL1;55445,TACR3;824,c.487_489delTGT;tmVar:p|DEL|487_489|C;HGVS:p.487_489delC;VariantGroup:17;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the @GENE$ gene (LQT6).",6610752,KCNH2;201,KCNE2;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,1
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Patient P0432 has a @VARIANT$ (@VARIANT$) mutation in @GENE$ and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23.",3125325,USH2A;66151,CDH23;11142,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; @VARIANT$), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A).",5887939,FZD1;20750,FAT4;14377,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Interestingly, from our cohort with specific clinical manifestations, which was not large in size, we identified two recurrent variants, GRIN2A @VARIANT$ and PLXNB2 @VARIANT$, which are rare variants in the general population. This finding supports the role of @GENE$ and @GENE$ in the molecular etiology of autism and developmental regression.",7463850,GRIN2A;645,PLXNB2;66630,c.28C > A;tmVar:c|SUB|C|28|A;HGVS:c.28C>A;VariantGroup:0;CorrespondingGene:2903,c.742C > T;tmVar:c|SUB|C|742|T;HGVS:c.742C>T;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0
"    Results We identified the digenic heterozygous mutations of KCNH2 p.307_308del (NM_001204798, @VARIANT$) and SCN5A p.R1865H (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. Subsequently, she occurred with obvious sinus arrest with persistent ventricular pacing of implantable cardioverter-defibrillator. The heterozygous SCN5Ap.R1865H was carried by her father and sister but not carried by I:2. II:1 carried with KCNH2 p.307_308del as a de novo mutation, but not existed in other family members. RNA secondary structure of KCNH2 @VARIANT$ showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the @GENE$ protein property, SCN5A p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index.   Conclusions The digenic heterozygous @GENE$ and SCN5A mutations were associated with young early-onset long QT syndrome and sinoatrial node dysfunction.",8739608,Nav1.5;22738,KCNH2;201,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.",5505202,PROKR2;16368,EMX1;55799,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"This hypothesis was further supported when a patient with Kallmann syndrome was discovered to carry the same PROKR2 heterozygous mutation as our proband, @VARIANT$, in combination with a second heterozygous mutation in @GENE$, @VARIANT$;p.A604T (NM_023110.2), thereby providing evidence for a digenic basis for the syndrome. Prokineticin 2 and @GENE$ are both expressed in the hypothalamus and pituitary, and reduced expression or activity of PROKR2 is implicated in both Kallmann syndrome and PSIS, perhaps because of the important role this signaling pathway plays in endocrine angiogenesis and neuronal migration in this region of the central nervous system.",5505202,FGFR1;69065,PROKR2;16368,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1810G>A;tmVar:c|SUB|G|1810|A;HGVS:c.1810G>A;VariantGroup:5;CorrespondingGene:2260;RS#:1412996644,0
Both the @VARIANT$ mutation in @GENE$ and the @VARIANT$ mutation in @GENE$ were within highly conserved residues and were predicted to be damaging by all three different bioinformatics algorithms (P = 0.999) (Supplemental Figs. S1and S2).,4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes @VARIANT$, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We provide evidence that mutations in the Cx26 and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,Cx31;7338,Cx26;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Our study suggests that the @GENE$-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Previous studies have shown @GENE$/TACI @VARIANT$ homozygous individuals are able to produce some IgG in vitro with APRIL stimulation alone. This is likely to be augmented by Toll-like receptor signalling with CpG as well as IL-4 and IL-21, in our experiments. As expected, his cells produce greater amounts of IgG through his intact T-cell-dependent pathway. The proband's son (III.1) carrying only the heterozygous @GENE$ @VARIANT$ mutation is also able to produce some IgG in vitro via activation of both pathways, but at much lower levels than his wild-type sister (III.2).",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,GJB3;7338,Cx26;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT5;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"We report digenic variants in @GENE$ and @GENE$ associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,PTK7;43672,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother.",8152424,PROKR2;16368,DDB1 and CUL4 associated factor 17;80067;1642,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"The c.1592G>A (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant @VARIANT$ (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in @GENE$/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant c.2075A>G (p.Asn692Ser) was identified in CDH2 (table 1), which encodes @GENE$, an integral mediator of cell-cell interactions.",6161649,BMP;55955,N-cadherin;20424,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the CCDC88C @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,DCC;21081,FGFR1;69065,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
" Finally, a subject with the heterozygous p.R143W mutation in @GENE$ (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES. However, neither @VARIANT$ in GJB2 nor p.D771N in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).",4998745,GJB2;2975,WFS1;4380,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2). While TIMP3 blocks VEGF/@GENE$ signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,VEGFR2;55639,RASA1;2168,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"However, when combined with the @GENE$ mutations, it led to a severe phenotype of thirteen missing teeth in the proband. This genetic synergism is also supported by the potential digenic inheritance of LRP6 and WNT10A mutations in Family 4. The proband, who had LRP6 p.(Asn1075Ser), p.(@VARIANT$), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of @GENE$ p.Thr1100Met protein. In addition, the genetic marker for MAP-tumors (KRAS @VARIANT$) was absent in this tumor, which points toward retained MUTYH repair activity. The combined inheritance of both genetic variants could still result in impaired repair of oxidative DNA damage. More extensive somatic mutation analysis to assess this was, however, not possible, because of low quality of the DNA sample and the unavailability of additional tumor material.         Next to MSH6 and @GENE$, CUX1 has been described as a cancer-driving gene. 18  CUX1 is implicated in inflammatory bowel disease and various cancer types, although primarily due to loss-of-function somatic mutations. 18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by OGG1. 20  The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool.",7689793,MSH6;149,MUTYH;8156,c.34G > T;tmVar:c|SUB|G|34|T;HGVS:c.34G>T;VariantGroup:12;CorrespondingGene:3845;RS#:587782084;CA#:13137,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,0
"Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"The Alanine754 is extremely conserved among orthologs of @GENE$ and @GENE$. The p.(@VARIANT$) mutation was predicted to be highly destabilizing. (C) Alignment of P4B3 domain (a.a. 1059-1097 of human LRP6). While @VARIANT$ is highly conserved among orthologs of LRP6 and LRP5, zebrafish LRP5 and Drosophila Arrow use threonine and aspartate, respectively, at this position.",8621929,LRP6;1747,LRP5;1746,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Asparagine1075;tmVar:p|Allele|N|1075;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and @VARIANT$ in MYO7A, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.5749G>T;tmVar:c|SUB|G|5749|T;HGVS:c.5749G>T;VariantGroup:155;CorrespondingGene:4647;RS#:780609120;CA#:224854968,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"  A recent study indicated that @GENE$ has an oligogenic inheritance rate of 77.7% in IHH, while our results indicated an overall oligogenic inheritance rate of 57.1% (8/14) among the detected families by simultaneously screening all causative and candidate genes. The results of our study and the PLXNA1 study consistently suggested that the rate of oligogenic inheritance of IHH genes varies and maintains at high levels. According to our data, eight patients had at least two IHH gene variants. Two patients carried three variants and one patient even carried four variants. Our data supported ""additive effect"" and ""cumulative mutation burden"" that were proposed in studies related to IHH. For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 @VARIANT$ and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant.",8152424,PLXNA1;56426,CDON;22996,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
More cellular and animal research is needed to further investigate whether the coexisting interaction of @GENE$ @VARIANT$ and @GENE$ @VARIANT$ increases the risk of the early-onset LQTS and sinoatrial node dysfunction.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ @VARIANT$ and SCRIB c.3979G>A).",5887939,PRICKLE4;22752,CELSR1;7665,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We previously reported two Probands harboring a homozygous, known pathogenic nonsense mutation in @GENE$ (@VARIANT$), both of whom exhibited uncharacteristically severe CH. Whole-exome sequencing in this kindred detected digenicity for a homozygous essential splice site DUOX1 mutation (@VARIANT$) in affected individuals, found to be pathogenic in vitro and likely contributing to the phenotypic severity. Materials and Methods All investigations were ethically approved and/or clinically indicated, being undertaken with patient or parental consent. Biochemical measurements Hormone measurements were made using local automated assays. Molecular genetic studies Detailed methods for performing and analyzing data from whole-exome sequencing and Sanger sequencing of the @GENE$ variant are provided in .",5587079,DUOX2;9689,DUOX1;68136,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (@GENE$) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,OPTN;11085,TANK-binding kinase 1;22742,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 @VARIANT$, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,PTK7;43672,SCRIB;44228,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663,0
"Somatic overgrowth associated with homozygous mutations in both @GENE$ and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, SEC23A c.1200G>C (@VARIANT$) and MAN1B1 @VARIANT$ (p.R334C), associated with congenital birth defects in two patients from a consanguineous family. Patients presented with carbohydrate-deficient transferrin, tall stature, obesity, macrocephaly, and maloccluded teeth. The parents were healthy heterozygous carriers for both mutations and an unaffected sibling with tall stature carried the heterozygous mutation in SEC23A only. Mutations in SEC23A are responsible for craniolenticosultura dysplasia (CLSD). CLSD patients are short, have late-closing fontanels, and have reduced procollagen (pro-COL1A1) secretion because of abnormal pro-@GENE$ retention in the endoplasmic reticulum (ER).",4853519,MAN1B1;5230,COL1A1;73874,p.M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"GJB2 Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected @GENE$ Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (@VARIANT$) (rs121908073), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,c.100C>T;tmVar:c|SUB|C|100|T;HGVS:c.100C>T;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002,1
"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,LAMA2;37306,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ @VARIANT$ and GFP-CYP1B1 E229K to immunoprecipitate HA-@GENE$ E103D and HA-TEK @VARIANT$, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated @GENE$ mutation (@VARIANT$; p.T468M) and a novel, potentially pathogenic missense @GENE$ variant (@VARIANT$; p.P340S) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,PTPN11;2122,SOS1;4117,c.1403 C > T;tmVar:c|SUB|C|1403|T;HGVS:c.1403C>T;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,c.1018 C > T;tmVar:c|SUB|C|1018|T;HGVS:c.1018C>T;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,1
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,FUS;2521,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0
"Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-@VARIANT$, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited @GENE$ T168fsX191 and TNFRSF13B/@GENE$ C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"It could be argued that the @GENE$/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family. Hence, priority should be given to identifying the @GENE$ @VARIANT$ mutation for preimplantation genetic diagnosis and/or chorionic villus sampling.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (@VARIANT$) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,0
"Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the @GENE$ (NM_000179.2: @VARIANT$, p.Thr1100Met) and @GENE$ (NM_001128425.1: c.536A > G, @VARIANT$) genes, while the other 20 genes could not be clearly linked to cancer predisposition.",7689793,MSH6;149,MUTYH;8156,c.3299C > T;tmVar:c|SUB|C|3299|T;HGVS:c.3299C>T;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,1
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: @VARIANT$ (p.410T>M), @GENE$: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,1
"The female CACNA1C-Q1916R mutation carriers with @GENE$-@VARIANT$ variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the CACNA1C-Q1916R mutation (IV-4) showed the ER ECG pattern. Other family members without the two variations had no ERS phenotypes. +/- heterozygous for variant; -/- wild type.       The correlation between genotype and phenotype. Phenotype penetrance @GENE$-@VARIANT$ +/-SCN5A-R1193Q +/-",5426766,SCN5A;22738,CACNA1C;55484,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: p.(C498R) and @VARIANT$; @GENE$: @VARIANT$).,6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,1
"We report digenic variants in SCRIB and @GENE$ associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,CELSR1;7665,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. Location analysis of missense changes showed that p.G1108E was located very close to the fourth PDZ domain (1109-1192) of SCRIB. The PDZ domains of human SCRIB are required for correct localization and physical interaction with other proteins, such as the core PCP protein VANGL2, which is required for transducing PCP signals. Herein we demonstrate that SCRIB variants combined with variants among other PCP genes might be associated with the observed NTD phenotypes in humans. However, pathogenic effect of these variants on protein function or on neural tube development need to be investigated in the future.   No reports are available in the literature on the contribution of digenic variants of @GENE$ and @GENE$ gene in the pathogenesis of NTDs.",5966321,CELSR1;7665,DVL3;20928,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB6;4936,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and @GENE$ (c.9921T>G).",3125325,CDH23;11142,USH2A;66151,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0
"This mutation changes codon 554 from arginine to a stop codon (@VARIANT$; @VARIANT$) and has been previously reported. The mother did not carry this luteinizing hormone/choriogonadotropin receptor (LHCGR) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, @GENE$, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants Trp228Cys and Pro226Leu activated the CYP17 promoter similar to wt. Transcriptional activity of @GENE$ variants on the CYP17A1 promoter.",5893726,SRY;48168,GATA4;1551,c.1160C>T;tmVar:c|SUB|C|1160|T;HGVS:c.1160C>T;VariantGroup:1;CorrespondingGene:2626;RS#:368991748;CA#:172121374,p.Arg554Stop;tmVar:p|SUB|R|554|X;HGVS:p.R554X;VariantGroup:1;CorrespondingGene:3973;RS#:368991748,0
"R583H+KCNE1 and cells co-expressing KCNQ1-WT+KCNE1 (V1/2: KCNQ1-WT+KCNE1, 31.8 +- 6.0 mV, n = 7; KCNQ1-@VARIANT$+KCNE1, 35.5 +- 5.9 mV, n = 8, p > 0.05; k: KCNQ1-WT+KCNE1, 16.86 +- 0.93 mV, n = 7; or KCNQ1-p.R583H+KCNE1, 15.38 +- 1.15 mV, n = 8, p > 0.05) (Figure 3). Based on these findings, we conclude that, unlike LQTS-associated mutations, the @GENE$-p.R583H variant does not severely affect the function of the channel. 2.3.2. KCNH2-p.C108Y Exhibits a Dominant-Negative Loss-of-Function Heterologous expression studies demonstrated that @GENE$-@VARIANT$ is a non-functional channel (Figure 4A).",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the S100A3 protein (c.229C>T; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in S100A13. Mutation name is based on the full-length @GENE$ (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the NRXN1 and NRXN2 proteins lead us to hypothesize that digenic variants in @GENE$ and @GENE$ contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the GJB2/235delC was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/GJB3, while the mother is heterozygous for the @GENE$/299-300delAT (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ @VARIANT$ mutation, but not the TNFRSF13B/TACI @VARIANT$ mutation.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"M1, @GENE$: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, CYP1B1: p.(E173*). M4, @GENE$: @VARIANT$. M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and @GENE$ @VARIANT$ mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
R583H variant was previously reported to be associated with LQTS; KCNH2-@VARIANT$ is a novel variant; and KCNH2-p.K897T and KCNE1-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the @GENE$ and @GENE$ channels.,5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"No mutations in SLC5A5, @GENE$, or @GENE$ gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: @VARIANT$ (p.Y138X) in one patient.",6098846,TPO;461,IYD;12352,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes @VARIANT$, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
The genotypes of the individuals for the @GENE$ and @GENE$ mutations are indicated below the symbols. Asterisk indicates the siblings whose biological samples were unavailable. Co-segregation of TEK @VARIANT$ and CYP1B1 @VARIANT$ was observed in two pedigrees and only a representative pedigree is shown.,5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"(b) The changed site of @GENE$ gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant DISCUSSION In our study, the proband with overlapped phenotypes of young early-onset LQTS and sinoatrial node dysfunction was first demonstrated to carry with the digenic heterozygous and pathogenic mutations of KCNH2 @VARIANT$ and SCN5A @VARIANT$. KCNH2 p.307_308del induced a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized, which thus mainly caused LQTS. The SCN5A p.R1865H slightly increased the molecular weight and aliphatic index, but reduced the instability index of Nav1.5 protein property, which potentially induced subsequent sinoatrial node dysfunction.   Genetic screening for LQTS is of great clinical value. The genotype is closely related to gene-specific epidemiology, risk stratification, and treatment of LQTS. Different channel mutations present their own electrocardiogram signature, typical presentations, and prognosis (Skinner et al.,; Wilde & Amin,). KCNH2 gene (@GENE$) encodes a voltage-sensitive channel protein mediating the rapid component of delayed rectifier K+ current (Kv11.1) (Butler et al.,).",8739608,SCN5A;22738,HERG;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,ubiquilin-2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"   The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and @GENE$ mutations.",7067772,EphA2;20929,SLC26A4;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"Therefore, in this study, @GENE$ @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ @VARIANT$ and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys.",3842385,WNT10A;22525,EDA;1896,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ @VARIANT$ to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%).",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"II: 1 carried the digenic heterozygous mutations of KCNH2 @VARIANT$ and @GENE$ @VARIANT$. I: 1 and II: 2 were heterozygous for SCN5A p.R1865H. Except II: 1, other family members did not carry @GENE$ mutation.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), @GENE$ @VARIANT$ (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,LAMA2;37306,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,0
"Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,CHD7;19067,FGFR1;69065,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Moderate iodine deficiency in association with double heterozygosity for DUOX1 and @GENE$ mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (@VARIANT$), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$).",5587079,DUOX2;9689,DUOX1;68136,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"In our studied family, SH107-225 with profound SNHL carried @VARIANT$ in GJB2 and a de novo variant, @VARIANT$ in @GENE$. @GENE$ as a molecular etiology was excluded from this subject, while digenic inheritance of SNHL can be proposed for this subject because the pathogenic potential of p.R341C was strongly supported by significant conservation of the p.R341 residue among various species and by the absence of this variant among the 666 control chromosomes from normal hearing control subjects.",4998745,MITF;4892,DFNB1;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Four genes (including AGXT2, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and @GENE$-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (@VARIANT$), RYR1 (@VARIANT$), @GENE$ (rs138172448), and DES (rs144901249) genes.",6180278,COL6A3;37917,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0
"@GENE$-@VARIANT$ was previously associated with a prolonged QT interval in several different populations and can alter the biophysical properties of mutant channels (current density, activation, inactivation, and recovery from inactivation) and exacerbate the IKr reduction caused by other KCNH2 mutations. KCNH2-p.K897T affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, KCNE1-p.G38S is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia. Nevertheless, in vitro studies demonstrated that the @GENE$-@VARIANT$ variant causes only a mild reduction of the delayed rectifier K+ currents.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the @VARIANT$ mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic @GENE$ p.T511M and SLC26A4 p.T410M mutations.",7067772,pendrin;20132,EPHA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, @VARIANT$, p.Tyr27His), @GENE$ (NM_018328.4, c.2000T>G, @VARIANT$), and NRXN1 (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,MBD5;81861,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: @VARIANT$ (p.R559W) and @GENE$: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.1675C > T;tmVar:c|SUB|C|1675|T;HGVS:c.1675C>T;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"(A) The EDA mutation @VARIANT$ and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"However, the proband's younger brother and father were heterozygous carriers of the @VARIANT$ mutation in the @GENE$ gene while they also carried the @VARIANT$ mutation in the @GENE$ gene; they did not display any signs of cutaneous findings or hematologic disorder.",2900916,GGCX;639,ABCC6;55559,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,1
"Similarly, human LRP6 Alanine754 was extremely conserved throughout vertebrate evolution of @GENE$ and @GENE$, while valine is used at this position in the Drosophila homolog, Arrow (Figure 5B). Structurally, the @VARIANT$ substitution altered its original interaction with Tyr763 and Leu796 and acquired an aberrant interaction with Ala752, which was predicted to cause destabilization. As for @VARIANT$, the residue was also highly conserved (Figure 5C).",8621929,LRP6;1747,LRP5;1746,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Asparagine1075;tmVar:p|Allele|N|1075;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of @GENE$ (c.1823-1G>C) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX2;9689,DUOX1;68136,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,0
"Given the complexity of the LQTS-related genetic background in our family, we functionally characterized only @GENE$-p.C108Y and @GENE$-@VARIANT$. Our data demonstrate that the activity of KCNH2-@VARIANT$ was significantly lower than that of the wild type.",5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"The LRP6 @VARIANT$ mutation is a rare variant with an MAF of 0.0024 in EAS. It was predicted to be ""possibly damaging"", with a PolyPhen-2 score of 0.767. The WNT10A mutation (c.499G>C, @VARIANT$), while being rare (MAF = 0.0003), was categorized as a benign variant (PolyPhen-2 score = 0.087). Segregation analysis showed that the father carried the two LRP6 variants, while the mother and the younger sister were both heterozygotes for the @GENE$ mutation. These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in LRP6 and WNT10A.       3.5. Predicted Structural Alterations and Pathogenicity of @GENE$ Missense Mutations Computational prediction of the structural impact for the five LRP6 missense mutations on protein stability demonstrated that p.Met168Arg, p.Ala754Pro, and p.Asn1075Ser were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively.",8621929,WNT10A;22525,LRP6;1747,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,rs148714379;tmVar:rs148714379;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) @GENE$:c.3329G>A (@VARIANT$) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"Similarly, SH170-377 carrying the @VARIANT$ mutation in @GENE$ also contained a previously reported homozygous @VARIANT$*36 mutant allele in @GENE$ (MYO15A) (NM_016239) (Table 1).",4998745,GJB2;2975,Myosin XVA;56504,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.Glu396Argfs;tmVar:p|FS|E|396|R|;HGVS:p.E396RfsX;VariantGroup:15;CorrespondingGene:51168;RS#:772536599;CA#:8423043,1
"(E) The EDA mutation @VARIANT$ and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in @GENE$ and @VARIANT$ in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"PREX2 activates PI3K signalling via inhibition of phosphatase and tensin homolog (@GENE$), and both germline and mosaic PTEN variants are associated with AVMs.   In patient AVM427, the de novo heterozygous missense variant @VARIANT$ (p.Asp1148Tyr) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates SMAD1 phosphorylation, thus activating BMP signalling. In addition to Smad1-mediated BMP signalling, ZFYVE16 also interacts with Smad4 to mediate Smad2-Smad4 complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, c.1891G>T (@VARIANT$), in EGFR (table 1). Oncogenic @GENE$ stimulates angiogenesis via the VEGF pathway.",6161649,PTEN;265,EGFR;74545,c.3442G>T;tmVar:c|SUB|G|3442|T;HGVS:c.3442G>T;VariantGroup:3;CorrespondingGene:9765,p.Glu631Ter;tmVar:p|SUB|E|631|X;HGVS:p.E631X;VariantGroup:8;RS#:909905659,0
"                              In the patient with the monoallelic mutation in exon 1 (@VARIANT$), additional studies were carried out to search for further genetic defects. A PCR amplicon containing GNRHR exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (rs373270328), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (c.[238C > T];[=]) (@VARIANT$) in the @GENE$ gene.         The @GENE$ frameshift mutation was identified in two different families and has not been reported before.",5527354,PROKR2;16368,GNRHR;350,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"These phenomenon indicate that the mutated @GENE$-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. @GENE$-c.1103C>T (@VARIANT$) variant impaired the catabolism of ADMA in EA.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
It turned out to be that only @GENE$-@VARIANT$ (p.Ala1012Val) and @GENE$-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.,5725008,SCAP;8160,AGXT2;12887,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,HS1BP3;10980,GNA14;68386,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,1
"In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling.",6161649,ENG;92,SCUBE2;36383,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (@VARIANT$; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in @GENE$. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,1
"25  The @GENE$ (NM_001036: c.7812C > G, @VARIANT$) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in @GENE$ might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients.",7689793,RYR3;68151,CAPN9;38208,p.Asn2604Lys;tmVar:p|SUB|N|2604|K;HGVS:p.N2604K;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (@VARIANT$) and @GENE$: c.1229C>A (@VARIANT$), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"However, we did not found any potential disease-related variant on @GENE$ of all 77 cases. SCAP-c.3035C>T (p.Ala1012Val) variant impaired the negative feedback mechanism of cholesterol synthesize in H293T cell lines SCAP-c.3035C>T (p.Ala1012Val) variant was introduced into @VARIANT$ cell lines by CRISPR-Cas9 methodology. After incubated with medium A (as described in the materials and methods section) for 6 hours, the wild-type goups showed a significant different distribution of SREBP-2 in cytoplasm and nucleus, (Figure 4A) while the @GENE$-mutated groups shows no such difference (Figure 4B). These phenomenon indicate that the mutated SCAP-c.3035C>T (p.Ala1012Val) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. AGXT2-c.1103C>T (p.Ala338Val) variant impaired the catabolism of ADMA in EA. hy926 cell lines AGXT2-@VARIANT$ (p.Ala338Val) variant was introduced into EA.",5725008,AGXT2;12887,SCAP;8160,H293T;tmVar:p|SUB|H|293|T;HGVS:p.H293T;VariantGroup:9;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,FUS;2521,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,0
"However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) @VARIANT$, and the rest were missense variants.",8152424,FGFR1;69065,CCDC88C;18903,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,0
KCNH2 @VARIANT$ may affect the function of @GENE$ channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. @GENE$ @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current.,8739608,Kv11.1;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"The SEMA7A gene variant was predicted as a VUS according to Varsome, whereas the @GENE$ gene variation was classified as benign. The SEMA7A variant [p.(Glu436Lys)] was absent in the 92 exomes of our local database (Supplementary Table 8). The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, ANOS1, DCC, PROP1, PLXNA1, and SEMA7A genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The DUSP6 gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PLXNA1;56426,PROKR2;16368,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0
"We identified a novel variant in BBS1 patient #10 c.1285dup (p.(Arg429Profs*72)) defined as pathogenic that segregates with phenotype together with @VARIANT$ (p.(Ser16Cys), defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, was identified in patient #3. @GENE$, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of BBS2 and @GENE$ lie in this portion.",6567512,BBS1;11641,BBS7;12395,c.46A > T;tmVar:c|SUB|A|46|T;HGVS:c.46A>T;VariantGroup:5;CorrespondingGene:582;RS#:772917364,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother.",8152424,PROKR2;16368,DCAF17;65979,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, @VARIANT$, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in WNT10A (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The LRP6 c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS. It was predicted to be ""possibly damaging"", with a PolyPhen-2 score of 0.767. The WNT10A mutation (c.499G>C, rs148714379), while being rare (MAF = 0.0003), was categorized as a benign variant (PolyPhen-2 score = 0.087). Segregation analysis showed that the father carried the two @GENE$ variants, while the mother and the younger sister were both heterozygotes for the @GENE$ mutation.",8621929,LRP6;1747,WNT10A;22525,c.379T>A;tmVar:c|SUB|T|379|A;HGVS:c.379T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Case 2 revealed a novel, heterozygous C to G change at position 5660 (c.5560C>G; @VARIANT$) of the LDL receptor-related protein 4 (LRP4) gene (OMIM 604270). This gene variant was also found in the mother and the maternal uncle. In case 3, a heterozygous change of cytosine to thymine was found at location 1660 of the LHCGR gene (OMIM 152790). This mutation changes codon 554 from arginine to a stop codon (c.1160C>T; @VARIANT$) and has been previously reported. The mother did not carry this luteinizing hormone/choriogonadotropin receptor (@GENE$) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, SRY, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the @GENE$ promoter revealed consistent results for comparing wt to mutant GATA4.",5893726,LHCGR;37276,CYP17;73875,p.Ser1887Cys;tmVar:p|SUB|S|1887|C;HGVS:p.S1887C;VariantGroup:2;CorrespondingGene:4038;RS#:73460019,p.Arg554Stop;tmVar:p|SUB|R|554|X;HGVS:p.R554X;VariantGroup:1;CorrespondingGene:3973;RS#:368991748,0
"In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes. The two mutations were in cis configuration, inherited together on the same chromosome from her father (Figure 1b).       The identification of fragment deletions in @GENE$. (a) The PCR quantification results of IID5.",6565573,COL4A3;68033,COL4A5;133559,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, @VARIANT$, p.Tyr27His), MBD5 (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"(D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in GJB2 allele harbored a single heterozygous p.A194T mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). This 2-year-old female showed severe autosomal recessive SNHL with a mean hearing threshold of 87.5 dB HL.   Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the p.T123N variant of @GENE$. The pathogenic potential of the @VARIANT$ variant is controversial.",4998745,gap junction protein beta 3;7338,GJB2;2975,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the @VARIANT$ mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that @GENE$ could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.",7067772,pendrin;20132,EphA2;20929,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, @VARIANT$, p.L86F, p.F112S, p.R127L, p.G149D, and @VARIANT$, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p. A85P;tmVar:p|SUB|A|85|P;HGVS:p.A85P;VariantGroup:78;CorrespondingGene:6012,p.R170W;tmVar:p|SUB|R|170|W;HGVS:p.R170W;VariantGroup:59;CorrespondingGene:1805,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the @GENE$/TACI @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 T168fsX191 gene. Exons coding E2A functional domains, activation domain 1 and 2 (AD1, AD2) and helix-loop-helix (HLH) domains are shown. (d) E2A (E47) protein expression was assessed by western blotting of lysates following 30 min PMA/ionomycin stimulation of PBMCS in the kindred, as indicated (U, unstimulated; S, stimulated). (e) PBMCs from the proband (II.2) and healthy control (HC) individuals (n=2) were unstimulated, or stimulated with PMA+ionomycin for 30 or 60 min as indicated, and cell lysates were analysed for p105 phosphorylation (P-p105, Ser933), expression of p105 and p50 by western blotting. @GENE$ was used as a protein loading control.",5671988,TNFRSF13B;49320,Beta-actin;133745,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Digenic inheritance of MSH6 and MUTYH variants in familial colorectal cancer Abstract We describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding @GENE$ @VARIANT$ and @GENE$ @VARIANT$ in, at least, three CRC patients diagnosed before 60 years of age.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,1
"This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2).",6161649,ENG;92,BMP;55955,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (@VARIANT$ of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
" In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).      In patient AVM467, the de novo heterozygous missense variant c.676G>A (@VARIANT$) was identified in @GENE$ (table 1).",6161649,CDH2;20424,IL17RD;9717,c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited @GENE$ T168fsX191 and TNFRSF13B/@GENE$ @VARIANT$ mutations are shown.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Among these four mutations, while the c.503T>G variant in @GENE$ is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 @VARIANT$, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The @GENE$ gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of PROKR2 were extracted, which revealed one common variant (@VARIANT$) in intron 1 with a MAF of 0.3 according to GnomAD.",8446458,DUSP6;55621,SEMA7A;2678,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.-9 + 342A > G;tmVar:c|SUB|A|-9+342|G;HGVS:c.-9+342A>G;VariantGroup:3;CorrespondingGene:128674;RS#:7351709,0
"The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes.     ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The p.Ala349Thr (c.1045G>A) mutation in exon 9 of EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in exon 3 of WNT10A were detected.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, @GENE$, @GENE$ and TPO).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B).",7248516,DUOX2;9689,DUOXA2;57037,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,0
"A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female @GENE$-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the CACNA1C-@VARIANT$ mutation led to a decreasing L-type calcium current and the protein expression defect.",5426766,SCN5A;22738,CACNA1C;55484,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (@GENE$ @VARIANT$).",8152424,DCC;21081,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,1
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.",7549550,MEOX1;3326,MYOD1;7857,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"A new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, @VARIANT$, was identified in patient #3. BBS1, @GENE$ and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS7;12395,BBS2;12122,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in @GENE$ (OMIM 612981; @VARIANT$, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in @GENE$ (OMIM 609890; rs748114415, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and ARHGEF19 (OMIM 612496; @VARIANT$, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,IMP4;68891,UBR4;10804,rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628,rs144638812;tmVar:rs144638812;VariantGroup:0;CorrespondingGene:128272;RS#:144638812,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ p.M170I and TAF15 p.R408C with SETX @VARIANT$ and @GENE$ @VARIANT$).,4293318,VAPB;36163,SETX;41003,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"We identified four genetic variants (@GENE$-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and @GENE$-@VARIANT$) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNQ1;85014,KCNE1;3753,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, @VARIANT$, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.494C>T;tmVar:c|SUB|C|494|T;HGVS:c.494C>T;VariantGroup:185;CorrespondingGene:4647;RS#:111033174;CA#:278676,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and @GENE$ p.R408C with SETX @VARIANT$ and SETX p.T14I).,4293318,ANG;74385,TAF15;131088,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:@VARIANT$; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.",4470809,TBK1;22742,OPTN;11085,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.2086G>A;tmVar:c|SUB|G|2086|A;HGVS:c.2086G>A;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,alsin;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"The @GENE$-@VARIANT$ variant is currently annotated as a mutation in the Human Gene Mutation Database (HGMD) database, having been identified in other LQTS subjects. @GENE$-@VARIANT$ was previously associated with a prolonged QT interval in several different populations and can alter the biophysical properties of mutant channels (current density, activation, inactivation, and recovery from inactivation) and exacerbate the IKr reduction caused by other KCNH2 mutations.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,0
"However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the @GENE$ @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,FGFR1;69065,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). A compound heterozygous TEK mutation (p.E103D and p.E300G) was also observed in 1 family (PCG38). However, the remaining 20 PCG cases harboring a single heterozygous TEK mutation did not carry any additional mutation in the other 35 adult and childhood glaucoma-associated genes (Supplementary Fig. 1; Supplementary Table 1). The co-occurrence of heterozygous @GENE$ and @GENE$ mutations as seen in our PCG cases were not observed in additional sets of POAG, ARS, Aniridia, and Peter's Anomaly patients.",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"During mesoderm development, the expression of MEOX1 is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.   CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified.",7549550,MYOD1;7857,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in @GENE$ was also identified.",7549550,RIPPLY1;138181,MYOD1;7857,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,1
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and p.(H395N); PITX2: @VARIANT$). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,UBQLN2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare @GENE$ missense variant (@VARIANT$).",5887939,PTK7;43672,CELSR2;1078,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR2;1078,FZD6;2617,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,KAL1;55445,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Anosmin-1 protein, encoded by the ANOS1 gene, is a type of extracellular matrix-related protein that plays an important role in the development and migration of olfactory nerve and GnRH neurons through the @GENE$ signalling pathway. Loss-of-function variants of the ANOS1 gene lead to KS, and its clinical phenotypes are relatively severe, including complete loss of puberty, infertility, cryptorchidism, and small phallus. In our study, @VARIANT$(p. Arg631*) and c.1267C > T(p. Arg423*) were the two reported variants, while @VARIANT$(p. Ser509fs) and c.1524del A(p. Ser509fs) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of @GENE$ gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function.",8796337,FGFR1;69065,KAl1;55445,c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223,c.1525delA;tmVar:c|DEL|1525|A;HGVS:c.1525delA;VariantGroup:13;CorrespondingGene:3730,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,VAPB;36163,FUS;2521,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Mutations in @GENE$ and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (c.229C>T; @VARIANT$) and d) the c.238-241delATTG (@VARIANT$) in @GENE$. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,1
"Proband 17 inherited CHD7 @VARIANT$ and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,CDON;22996,FGFR1;69065,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"A single control also had two mutations, @VARIANT$ in ALS2 and @VARIANT$ in TARDBP. ALS2 pathogenicity has only been observed in homozygotes, and this individual was heterozygous. Furthermore, the TARDBP variant has been previously identified in controls and has unclear status, although it is associated with abnormal localization and aggregation of TARDBP. What constitutes a pathogenic combination of mutations is debatable as some variants are of uncertain significance, and the combination of a pathogenic variant with one of uncertain significance has been considered oligogenic inheritance by some. Similarly, variation in @GENE$ or @GENE$ is generally considered a weak contributor to ALS risk, and missense variants in SPG11 are often benign unless resulting in loss of function.",5445258,ANG;74385,NEFH;40755,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"Two potential disease-causing mutations were identified: (d) @GENE$: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) LAMA3 missense mutation c.1559G>A/@VARIANT$. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (ENAM and @GENE$) mutations.",6785452,ENAM;9698,LAMA3;18279,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, @VARIANT$ and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father).",3975370,IL10RA;1196,NOD2;11156,c.475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,0
"We identified four genetic variants (KCNQ1-p.R583H, @GENE$-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$) in an LQTS family.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
"Furthermore, this @GENE$-@VARIANT$ mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (p.R1193Q, @VARIANT$) with an allele frequency of 0.006215 (data form ExAC) in @GENE$ was also found in the proband (Fig 2D, Table 2).",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,rs41261344;tmVar:rs41261344;VariantGroup:7;CorrespondingGene:6331;RS#:41261344,1
"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB @VARIANT$ and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,SOD1;392,VAPB;36163,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Based on these results, we assume that the @GENE$ R261H variant is more frequent in the Hungarian population (both in patients and controls) than in other populations, although further large cohort studies are needed to confirm this conclusion. This study provides additional evidence that NEK1 missense variants may contribute to the development of sALS.    Missense variants in the NEFH gene were detected in four patients: the T338I variant in two cases and the R148P and @VARIANT$ variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS.",6707335,NEK1;14376,GRN;1577,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,0
"The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly). Both fetuses inherited the maternal @GENE$ missense variant, in addition to the paternal p.(Ser872Gly) variant in PKD1, while only one fetus inherited the p.(Arg872Gly) PKD2 variant.",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,0
"Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ @VARIANT$ to immunoprecipitate HA-TEK E103D and HA-@GENE$ @VARIANT$, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,1
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::@GENE$ (@VARIANT$), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"The pathogenicity of the @VARIANT$ mutation in @GENE$  is, however, questionable since we found it in five alleles from the control population. The c.5601delAAC mutation in @GENE$, leading to an in frame-deletion of a threonine residue (@VARIANT$) within the intracellular domain of the protocadherin-15 CD1 isoform, also warrants a special mention.",3125325,CDH23;11142,PCDH15;23401,p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387,p.T1868del;tmVar:p|DEL|1868|T;HGVS:p.1868delT;VariantGroup:223;CorrespondingGene:65217,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"On the other hand, mutant GFP-@GENE$ @VARIANT$ and R368H showed perturbed interaction with HA-TEK. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of @GENE$ (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327,0
"A subject with Waardenburg syndrome type II (WS2) in a large Chinese population had both @GENE$ and @GENE$ mutations in a compound heterozygous state. The profound SNHL in the subject may have been caused by the digenic effect of GJB2 and MITF mutations, although the WS2 phenotype was caused by the MITF mutation. In our studied family, SH107-225 with profound SNHL carried @VARIANT$ in GJB2 and a de novo variant, @VARIANT$ in MITF.",4998745,MITF;4892,GJB2;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,1
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin @VARIANT$, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"In addition, we have confirmed that immunoreactive signal corresponding to the anti-ephrin-B2 antibody was colocalized with that to the anti-@GENE$ antibody in the inner ear (Supplementary Fig. 3g). These results suggest an important role of ephrin-B2 as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1.           Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated @GENE$. myc-pendrin A372V, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, @VARIANT$ and @VARIANT$ was not affected.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"While tagged versions of EphA2 @VARIANT$ and EphA2 T511M were effectively precipitated with Fc-fusion ephrin-A1 compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down @GENE$ G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 G355R and EphA2 T511M with pendrin induced by ephrin-B2 but not @GENE$ was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as @VARIANT$, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum.",7067772,EphA2;20929,ephrin-A1;3262,G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0
"The side chains of R/@VARIANT$ and A/T2282 are shown as sticks, and the other residues are shown as lines. (D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.R566L, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$, p.R50C).",7279190,FLNB;37480,TTC26;11786,L566;tmVar:p|Allele|L|566;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260,0
"Most had @GENE$ repeat expansion combined with another mutation (e.g. VCP @VARIANT$ or @GENE$ A321V; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in ALS2 and A90V in TARDBP.",5445258,C9orf72;10137,TARDBP;7221,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,0
"Mutations in NRXN1 and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, p.Arg896Trp) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the @GENE$ repeat expansion or a missense variant in SOD1 in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX @VARIANT$ and @GENE$ p.T14I).",4293318,C9ORF72;10137,SETX;41003,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"        Molecular Data All three probands carry two heterozygous variants: @GENE$, c.1175C>T (@VARIANT$), and TIA1, @VARIANT$ (p.Asn357Ser). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and SQSTM1 variants have been reported in multiple databases.",5868303,SQSTM1;31202,TIA1;20692,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"However, none of these signs were evident from metabolic work of the patient with PHKA1 @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 @VARIANT$ and NDUFS8 I126V variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in @GENE$ and @GENE$ are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects.",6072915,RYR1;68069,CACNA1S;37257,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,0
"The other two LRP6 variants, c.2450C>G (p.Ser817Cys) and c.4333A>G (@VARIANT$), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the WNT10A mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance. Segregation analysis of the parent-child trio revealed that the father, who was hypodontic, carried all three LRP6 variants but not the WNT10A mutation, which was found in the mother. This segregation pattern of mutations suggested a plausible synergetic effect from the @GENE$ and @GENE$ mutations, which caused thirteen missing teeth in the proband.",8621929,LRP6;1747,WNT10A;22525,p.Met1445Val;tmVar:p|SUB|M|1445|V;HGVS:p.M1445V;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and @GENE$ (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,UNC13B;31376,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"The @GENE$ and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. Allele frequency for @VARIANT$ within the population was calculated from exome sequencing of 2000 individuals and was found to be 0.1% (unpublished data from the Saudi Human Genome Project; www.saudigenomeprogram.org).",6637284,ISG20L2;12814,SETDB1;32157,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"Since @GENE$ is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"Moreover, gain-of-function mutation of @GENE$ commonly induced LQTS, while loss-of-function mutation of SCN5A ordinary led to sinoatrial node dysfunction, atrioventricular block, atrial fibrillation and cardiomyopathy (e.g., ARVC/D; Blana et al.,; Han et al.,). Therefore, in this study, SCN5A @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and @VARIANT$ (p.Asn118Ser) in MFSD8. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (EHMT1 c.1513G > A at a rate of 4.95 x 10-5, @GENE$ c. 353A > G at a rate of 8.24 x 10-6).",7463850,EHMT1;11698,MFSD8;115814,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,SEMA7A;2678,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, @VARIANT$; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,p.Ser817Cys;tmVar:p|SUB|S|817|C;HGVS:p.S817C;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,VAPB;36163,FUS;2521,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/@GENE$ C104R mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI @VARIANT$ mutations are shown.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Detection of mutations Screening of the @GENE$, @GENE$, EDAR, and EDARADD genes was performed by direct sequencing of five PCR fragments for WNT10A, eight PCR fragments for EDA, ten PCR fragments for EDAR, and eight PCR fragments for EDARADD, which cover the entire cDNA including exons and intron-exon junctions of more than 100 base pairs. We compared all primer sequences to the whole-genome assembly in the ENSEMBL database to verify their uniqueness against gene families. Primer sequences are available upon request. Protein structure analysis We performed protein structure analysis on the two WNT10A mutations (p.R171C and @VARIANT$) and two novel EDA mutations (p.G257R and @VARIANT$) that were identified in this study.",3842385,WNT10A;22525,EDA;1896,p.G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.I312M;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Neither the @VARIANT$ nor the @VARIANT$ variant has been reported as a mutation of a compound heterozygote in patients diagnosed with a myopathy secondary to mutations in either the DES or CAPN genes. Discussion The patient's history, clinical examination, EMG testing, muscle biopsy results, and the lack of response to any therapy suggest that he does not have an inflammatory myopathy but rather a genetic disorder. Mutations in CAPN3 and DES genes result in LGMD inherited in an autosomal recessive pattern. Homozygous or compound heterozygous mutations in the @GENE$ and @GENE$ genes cause LGMD 2A and LGMD 2R, respectively.",6180278,CAPN3;52,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"The @GENE$ and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. Allele frequency for @VARIANT$ within the population was calculated from exome sequencing of 2000 individuals and was found to be 0.1% (unpublished data from the Saudi Human Genome Project; www.saudigenomeprogram.org).",6637284,ISG20L2;12814,SETDB1;32157,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"However, significantly more pro-COL1A1 was secreted in fibroblasts with heterozygous mutations in both @GENE$ and @GENE$ (P < 0.05, ANOVA), when compared with wild type (Supplemental Fig. S7). Surprisingly, mutant fibroblasts showed levels of intracellular and secreted pro-COL1A1 comparable with those of wild-type cells. Our data indicate that a normal level of MAN1B1 is required to prevent secretion of abnormally folded pro-COL1A1. These data also indicate that an alternate pathway is used for quality control of pro-COL1A1 when MAN1B1 alpha-mannosidase activity is reduced. DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"In addition, we found an elevated frequency (8%) of heterozygous and rare @GENE$ variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (@GENE$: @VARIANT$, p.(H395N); and PITX2: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and p.(H395N); PITX2: @VARIANT$).",6338360,PITX2;55454,FOXC2;21091,c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a).",8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the 497A>G (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the @VARIANT$ (A194T) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of Cx31 and Cx26 in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against @GENE$ (a) and @GENE$ (b).,2737700,Cx26;2975,Cx31;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,580G>A;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Interestingly, we identified 5 patients (4.8%) with variants in @GENE$ (OPTN) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,optineurin;11085,TANK-binding kinase 1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6.",6610752,LQT2;201,KCNE2;71688,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI @VARIANT$ mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"We identified a novel variant in BBS1 patient #10 c.1285dup (p.(Arg429Profs*72)) defined as pathogenic that segregates with phenotype together with @VARIANT$ (p.(Ser16Cys), defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, was identified in patient #3. @GENE$, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of BBS2 and BBS7 lie in this portion. The variant in @GENE$ is noteworthy, since very few Bardet-Biedl cases are reported in the literature.",6567512,BBS1;11641,BBS7;12395,c.46A > T;tmVar:c|SUB|A|46|T;HGVS:c.46A>T;VariantGroup:5;CorrespondingGene:582;RS#:772917364,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ @VARIANT$ and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant @VARIANT$).",5887939,FZD6;2617,FAT4;14377,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"Among these four mutations, while the @VARIANT$ variant in @GENE$ is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ @VARIANT$, rs147680216) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The two variants chr18:77170979 G>A for @GENE$ and chr1:228462101 G>A for @GENE$ lead to novel missense variants, @VARIANT$ and @VARIANT$ respectively.",5611365,NFATC1;32336,OBSCN;70869,p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Moller et al. reported an index case with digenic variants in @GENE$ (@VARIANT$) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,MYH7;68044,MYBPC3;215,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,1
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; @VARIANT$, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,g.124339A>G;tmVar:g|SUB|A|124339|G;HGVS:g.124339A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Most had C9orf72 repeat expansion combined with another mutation (e.g. @GENE$ @VARIANT$ or TARDBP A321V; Supplementary Table 6). A single control also had two mutations, P372R in @GENE$ and @VARIANT$ in TARDBP.",5445258,VCP;5168,ALS2;23264,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,ubiquilin-2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and @GENE$ (@VARIANT$).",3125325,CDH23;11142,USH2A;66151,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
   Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the @GENE$ gene and in exon 4 (@VARIANT$; p.Pro291Arg) of the @GENE$ gene were identified.,8306687,GCK;55440,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. On the contrary, in the mother, some other factors, including unknown genetic modifiers, could counteract the functional impairment of mutant channels, thereby protecting the asymptomatic @GENE$-@VARIANT$ mutation-positive subject from arrhythmia susceptibility.",5578023,KCNQ1;85014,KCNH2;201,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
Pathogenic effects of @GENE$ @VARIANT$ and @GENE$ @VARIANT$ variants remain unknown.,6072915,GBE1;129,NDUFS8;1867,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0
"2.3. Functional Consequences of the @GENE$-@VARIANT$ and @GENE$-p.C108Y Variants To investigate the functional consequences of KCNQ1-p.R583H and KCNH2-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"We finally found evidence of four potential novel candidate genes contributing to IHH: coiled-coil domain containing 88C (CCDC88C), cell adhesion associated, oncogene regulated (CDON), @GENE$ (GADL1), and sprouty related EVH1 domain containing 3 (SPRED3). The CCDC88C missense variant @VARIANT$ was heterozygous in case P05. CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and @GENE$ c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,glutamate decarboxylase like 1;45812,FGFR1;69065,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and @GENE$/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant @GENE$ T168fsX191 gene.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, @GENE$ p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,ANG;74385,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by @GENE$. 20  The identified @GENE$ (NM_001202543: c.1438A > G, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, @VARIANT$) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,OGG1;1909,CUX1;22551,p.Asn2604Lys;tmVar:p|SUB|N|2604|K;HGVS:p.N2604K;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in GJB6. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, rs147680216) in EAS. The novel @GENE$ c.503T>G mutation substitutes the hydrophobic methionine168 for an arginine (@VARIANT$) and is predicted to be ""probably damaging"", with a PolyPhen-2 score of 1. The other two LRP6 variants, c.2450C>G (p.Ser817Cys) and c.4333A>G (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the WNT10A mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance.",8621929,WNT10A;22525,LRP6;1747,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"It was shown that digenic variants in CYP1B1 and @GENE$ contribute to PCG and that variants in both FOXC1 and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely @VARIANT$, p.P79T, p.S82T, p. A85P, p.L86F, p.F112S, p.R127L, p.G149D, and @VARIANT$, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,MYOC;220,PITX2;55454,p.Q70Hfs*8;tmVar:p|FS|Q|70|H|8;HGVS:p.Q70HfsX8;VariantGroup:8;CorrespondingGene:6012,p.R170W;tmVar:p|SUB|R|170|W;HGVS:p.R170W;VariantGroup:59;CorrespondingGene:1805,0
"(A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the @GENE$ locus.",4998745,GJB6;4936,DFNB1;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6.",6610752,KCNH2;201,KCNE2;71688,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in MYO7A and @VARIANT$ in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous @VARIANT$ transition in exon 20, which results in an alanine to a serine (Ala771Ser) in @GENE$. Another variation, 158-1G>A in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,2311G>T;tmVar:c|SUB|G|2311|T;HGVS:c.2311G>T;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,TOR2A;25260,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for REEP4 @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates                TOR2A missense variant A @GENE$ nonsynonymous SNV (c.568C>T [NM_130459.3], @VARIANT$ [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,BSP+;3644,TOR2A;25260,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of @GENE$ and/or @GENE$ expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism.",4470809,OPTN;11085,TBK1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX2;9689,DUOX1 and -2;53905;50506,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"        Molecular Data All three probands carry two heterozygous variants: SQSTM1, c.1175C>T (@VARIANT$), and TIA1, @VARIANT$ (p.Asn357Ser). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and @GENE$ variants have been reported in multiple databases.",5868303,TIA1;20692,SQSTM1;31202,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"We report digenic variants in @GENE$ and PTK7 associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,PTK7;43672,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Sequence alterations were detected in the @GENE$ (@VARIANT$), RYR1 (rs143445685), CAPN3 (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,COL6A3;37917,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (@VARIANT$), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,SPG11;41614,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form.",6707335,GRN;1577,SIGMAR1;39965,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.",3842385,WNT10A;22525,EDA;1896,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The proband of Family 3 was a compound heterozygote of p.(@VARIANT$) and p.(Ser127Thr) mutations and had fourteen missing teeth, while his father, who carried the p.(Ala754Pro) mutation, exhibited only two. Interestingly, the mother was homozygous for the p.(@VARIANT$) mutation and had all permanent teeth excepting third molars, suggesting that the variant might serve as a putative genetic modifier while not being disease-causing itself. These observations of digenic inheritance and genetic modification are supported by the significant role of @GENE$ signaling in tooth development and a direct molecular interaction between @GENE$ and LRP6.",8621929,WNT;22529,WNT10A;22525,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, @VARIANT$) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,ubiquilin-2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous @GENE$ mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Four genes (including @GENE$, ZFHX3, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only @GENE$-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,AGXT2;12887,SCAP;8160,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,TARDBP;7221,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"We found that GATA4 variant @VARIANT$ lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, @GENE$ variants @VARIANT$ and Pro226Leu activated the @GENE$ promoter similar to wt.",5893726,GATA4;1551,CYP17;73875,Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) @GENE$:@VARIANT$ (p.R1110Q) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,c.3329G>A;tmVar:c|SUB|G|3329|A;HGVS:c.3329G>A;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"Specifically, heterozygous missense mutations in neighboring residues A435 (@VARIANT$;p.A435T; rs318240760) and R448 (c.1343G>A;p.R448Q; rs144440500) have been identified in each of two individuals with idiopathic hypogonadotropic hypogonadism and normosmia. In addition, in a different individual, the @GENE$ p.A435T mutation was identified in association with a mutation in a second gene, @GENE$ (c.275T>C;@VARIANT$; MIM 138850; NM_000406.2), implicating digenic inheritance of this disorder as well.",5505202,WDR11;41229,GNRHR;350,c.1303G>A;tmVar:c|SUB|G|1303|A;HGVS:c.1303G>A;VariantGroup:0;CorrespondingGene:55717;RS#:318240760;CA#:130157,p.L92P;tmVar:p|SUB|L|92|P;HGVS:p.L92P;VariantGroup:8;CorrespondingGene:2629;RS#:1141815,0
"A single @GENE$ mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Genetic screening of the KCNH2 gene also revealed the @GENE$-c.A2690C (@VARIANT$) common variant (MAF = 0.187). This variant was previously reported to be a possible negative modifier of IKr that is able to alter channel kinetics, predispose to arrhythmic events, affect the repolarization process, and alter the length of the QT interval. Another common variant in the @GENE$ gene (@VARIANT$) results in the substitution of the glycine residue with serine at position 38 (p.G38S) and is located in the C-terminal cytoplasmic domain.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,c.G112A;tmVar:c|SUB|G|112|A;HGVS:c.112G>A;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"However, this genomic @VARIANT$ variant was not seen in the NCBI SNP database or in 372 ethnically-matched controls, arguing against a polymorphism.   This patient also was found to have a novel, heterozygous @GENE$ nonsense mutation @VARIANT$ not seen in 180 controls (Figure 1C; Table 1). Trp275 lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this G-protein coupled receptor, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in CHD7, FGF8, FGFR1, @GENE$, PROKR2, TAC3, KAL1, GNRHR, GNRH1, or KISS1R.",3888818,TACR3;824,PROK2;9268,c.1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"(A) Segregation of the @GENE$-@VARIANT$, KCNH2-p.C108Y, @GENE$-p.K897T, and KCNE1-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, @VARIANT$ in @GENE$ and @VARIANT$ in @GENE$, and one novel variant in S100A13, were identified.",6637284,SETDB1;32157,S100A3;2223,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of MSH6 @VARIANT$ protein. In addition, the genetic marker for MAP-tumors (@GENE$ @VARIANT$) was absent in this tumor, which points toward retained MUTYH repair activity. The combined inheritance of both genetic variants could still result in impaired repair of oxidative DNA damage. More extensive somatic mutation analysis to assess this was, however, not possible, because of low quality of the DNA sample and the unavailability of additional tumor material.         Next to MSH6 and MUTYH, CUX1 has been described as a cancer-driving gene. 18  @GENE$ is implicated in inflammatory bowel disease and various cancer types, although primarily due to loss-of-function somatic mutations.",7689793,KRAS;37990,CUX1;22551,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.34G > T;tmVar:c|SUB|G|34|T;HGVS:c.34G>T;VariantGroup:12;CorrespondingGene:3845;RS#:587782084;CA#:13137,0
"This is likely to be augmented by Toll-like receptor signalling with CpG as well as @GENE$ and @GENE$, in our experiments. As expected, his cells produce greater amounts of IgG through his intact T-cell-dependent pathway. The proband's son (III.1) carrying only the heterozygous TCF3 T168fsX191 mutation is also able to produce some IgG in vitro via activation of both pathways, but at much lower levels than his wild-type sister (III.2). His cells produced higher levels of IgG and IgM than his mother (II.2, who bears both the TNFRSF13B/TACI @VARIANT$ and TCF3 @VARIANT$ mutations).",5671988,IL-4;491,IL-21;11032,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Notably, the common variants @GENE$-@VARIANT$ and @GENE$-@VARIANT$ were previously reported to produce more severe phenotypes when combined with disease-causing alleles.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"  Recently, Gifford et al., identified three missense variants in @GENE$ (@VARIANT$), @GENE$ (@VARIANT$), and NKX2-5 (Ala119Ser) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MKL2;40917,MYH7;68044,Gln670His;tmVar:p|SUB|Q|670|H;HGVS:p.Q670H;VariantGroup:2;CorrespondingGene:57496,Leu387Phe;tmVar:p|SUB|L|387|F;HGVS:p.L387F;VariantGroup:4;CorrespondingGene:4625,1
"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,TOR2A;25260,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The absence of variant combinations involving the PROKR2 gene variant @VARIANT$ excludes its implication in digenic inheritance in the index case (HH12). Furthermore, since the variant is novel and has no functional evidence of pathogenicity, it is likely to be benign. Further molecular studies are needed to prove the deleterious character of the PROKR2 Lys205del variant. Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(Val114Leu)]. Such findings bring into question their involvement in disease expression in HH12. The @GENE$ variant [p.(Glu436Lys)] was predicted as VUS by Varsome. Sanger validation revealed the absence of this mutation in the healthy mother. The SEMA7A and @GENE$ genes were implicated in a digenic combination classified as ""dual molecular diagnosis"" by ORVAL.",8446458,SEMA7A;2678,DUSP6;55621,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"Patient P0418 carries a nonsense mutation in @GENE$ (p.S5030X) and a missense mutation in MYO7A (p.K268R), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,CDH23;11142,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (p.Gln106Arg, at 0.2%; @VARIANT$, at 0.0008%; p.Arg262Gln at 0.2%; and @GENE$ @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (GNRHR/PROKR2) heterozygous mutation. The @GENE$ missense mutations identified in this study have been previously reported in other nCHH patients, namely p.Gln106Arg, p.Val134Gly, p.Arg139Cys, p.Arg262Gln and p.Tyr283His.",5527354,PROKR2;16368,GNRHR;350,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"Additionally, three DUOXA2 variants were found in 3/21 patients (14%), and a known heterozygous variant in @GENE$ was found in one patient. No mutations in SLC5A5, TPO, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) @GENE$:@VARIANT$ (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,SLC26A4;20132,DUOX2;9689,c.3329G>A;tmVar:c|SUB|G|3329|A;HGVS:c.3329G>A;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"KAT2B @VARIANT$ is a loss-of-function mutation in Drosophila Drosophila Gcn5 is homologous with KAT2B and its paralog KAT2A. Gcn5E333st hemizygous animals died at late larval stage/early pupal stage as previously reported for this null mutation. The expression of Drosophila Gcn5 (hereafter referred to as Gcn5 WT) with tub-GAL4 or another ubiquitous driver (daughterless (da)-@GENE$) led to a full rescue (S3B Fig and Fig 3C). By contrast, the expression of human @GENE$ and KAT2B, either alone or in combination, did not restore the viability of the mutant (Fig 3C), suggesting that the human orthologs have evolved in structure and function in comparison to Gcn5. As the mutated amino acid in KAT2B, F307, is conserved in Drosophila Gcn5 (corresponding to Gcn5 @VARIANT$), we re-expressed Gcn5 F304S in the Gcn5E333st hemizygous background (Gcn5 F304S).",5973622,GAL4;21239,KAT2A;41343,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,F304;tmVar:p|Allele|F|304;VariantGroup:6;CorrespondingGene:39431,0
"     In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (p.Gly226Ser) was identified in @GENE$ (table 1). IL17RD is highly expressed in vessel endothelial cells and vascularised organs, where it inhibits fibroblast growth factor (FGF) and plays critical roles in endothelial cell proliferation and angiogenesis. In contrast to FGF inhibition, overexpression of IL17RD attenuates the degradation of epidermal growth factor recepter (EGFR) and enhances downstream @GENE$ signalling (figure 3).    In patient AVM457, a de novo heterozygous missense variant c.3355G>A (@VARIANT$) with a robust deleterious damaging predictions (SIFT=0.1, PolyPhen2=0.99, GERP++=4.33, CADD=29.3) was identified in PREX2 (table 1).",6161649,IL17RD;9717,MAPK;37670,c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588,p.Ala1119Thr;tmVar:p|SUB|A|1119|T;HGVS:p.A1119T;VariantGroup:5;CorrespondingGene:80243;RS#:1212415588,0
"          In a second example, we identified a monoallelic change in @GENE$ (@VARIANT$, p.Arg227Gln, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of SRD5A2, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014).",5765430,SRD5A2;37292,SF1;138518,c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442,single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536,1
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,FGFR1;69065,DCC;21081,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,1
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"    Sanger sequencing Sanger sequencing was performed on available samples for confirmation of @GENE$ and MYO6 variants in family members to perform segregation analysis. Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"Protein structure analysis We performed protein structure analysis on the two WNT10A mutations (p.R171C and @VARIANT$) and two novel @GENE$ mutations (p.G257R and @VARIANT$) that were identified in this study. For @GENE$, the conservation of residues in sequences was determined to predict the influence of the two mutations.",3842385,EDA;1896,WNT10A;22525,p.G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.I312M;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,CCNF;1335,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6.",6610752,KCNH2;201,KCNE2;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Prompted by the idea of an oligogenic mechanism of disease we further looked at the presence of more frequent variants (MAF <0.1%) in individuals already harboring extremely rare variants in OPTN and TBK1 and noted that case A carrying the @VARIANT$ nonsense variant in OPTN, is compound heterozygote for mutations in @GENE$ as it also carries the rare variant @VARIANT$ (NM_001008211.1:c.1442C>T) in OPTN (MAF=0.0116% in ESP - CADD_Phred score: 34). In order to evaluate the likelihood of OPTN and TBK1 to harbor rare compound heterozygous variants or double mutations, we applied the same stringent filters that we used for our FTLD-TDP cases to our control dataset (155 Harvard PGP controls and 100 parents of intellectual disability patients). Using these filtering settings, no variants in OPTN or @GENE$ were detected in any of our control datasets which emphasizes that the presence of rare double hits in our FTLD-TDP cohort is unlikely to have occurred by chance alone.",4470809,OPTN;11085,TBK1;22742,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Ala481Val;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT5;71688,LQT2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"        Ebermann et al. described a USH2 patient with ""digenic inheritance."" a heterozygous truncating mutation in GPR98, and a truncating heterozygous mutation in @GENE$ (PDZD7), which is reported to be a cause of USH. Our USH1 patient (Case #4) had segregated MYO7A:@VARIANT$ and @GENE$:@VARIANT$. Molecular analyses in mouse models have shown many interactions among the USH1 proteins.",3949687,PDZ domain-containing 7;129509,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in @GENE$ (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, @GENE$, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,TYRO3;4585,ROR2;55831,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6.",6610752,LQT2;201,KCNE2;71688,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, @VARIANT$), @GENE$ @VARIANT$ (NM_000426, c.G2881A), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,LAMA2;37306,KCNH2;201,c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), @GENE$: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG @VARIANT$, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,DCTN1;3011,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in @GENE$. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(Ser123Thr), and a second variant in PKD2, p.(@VARIANT$).",7224062,PKD2;20104,PKD1;250,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and @GENE$ (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,1
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) @GENE$:@VARIANT$ (p.R1110Q) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,c.3329G>A;tmVar:c|SUB|G|3329|A;HGVS:c.3329G>A;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"Interestingly, we identified 5 patients (4.8%) with variants in @GENE$ (OPTN) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,optineurin;11085,TANK-binding kinase 1;22742,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (rs143445685), @GENE$ (rs138172448), and DES (@VARIANT$) genes. We hypothesized that the inheritance pattern could follow a digenic pattern of inheritance. Screening for these polymorphisms in an unaffected sister revealed the presence of all these same variants except for that in the CAPN3 gene. All variants were studied to determine their frequency and if they had been previously reported as mutations. They were also subjected to protein modeling programs, including SIFT, PolyPhen, and MutationTaster. This analysis indicated that the CAPN3 variant c.1663G>A (rs138172448), which results in a @VARIANT$ change, and the @GENE$ gene variant c.656C>T (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging.",6180278,CAPN3;52,DES;56469,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,p.Val555Ile;tmVar:p|SUB|V|555|I;HGVS:p.V555I;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and @GENE$ (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:@VARIANT$; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.2086G>A;tmVar:c|SUB|G|2086|A;HGVS:c.2086G>A;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,UBQLN2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"This sequence variant changes a glutamine codon (CAG) to a translation termination codon (TAG) at position 1252 (NP_002327.2:@VARIANT$) and will likely subject the altered transcript to nonsense mediated decay. The mutation is not documented in the Genome Aggregation Database (gnomAD) or the Taiwan BioBank database. In addition, a missense sequence variant in WNT10A (NG_012179.1:g.6853G>A; NM_025216.3:c.338G>A; NP_079492.2:@VARIANT$) was also identified (Figure S1A). This variant, designated as rs749324327, has a minor allele frequency (MAF) of ~0.0004 in East Asian (EAS) populations and is predicted to be ""benign"", with a PolyPhen-2 score of 0.015. No potential pathogenic mutations were detected in other candidate genes of FTA. Further Sanger sequencing and segregation analysis indicated that the @GENE$ and @GENE$ mutations were both inherited from the father.",8621929,LRP6;1747,WNT10A;22525,p.Gln1252*;tmVar:p|SUB|Q|1252|*;HGVS:p.Q1252*;VariantGroup:15;CorrespondingGene:4040,p.Arg113His;tmVar:p|SUB|R|113|H;HGVS:p.R113H;VariantGroup:3;CorrespondingGene:80326;RS#:749324327;CA#:2113880,1
"The other two LRP6 variants, @VARIANT$ (p.Ser817Cys) and c.4333A>G (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the WNT10A mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance. Segregation analysis of the parent-child trio revealed that the father, who was hypodontic, carried all three LRP6 variants but not the WNT10A mutation, which was found in the mother. This segregation pattern of mutations suggested a plausible synergetic effect from the @GENE$ and @GENE$ mutations, which caused thirteen missing teeth in the proband.",8621929,LRP6;1747,WNT10A;22525,c.2450C>G;tmVar:c|SUB|C|2450|G;HGVS:c.2450C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"Since @GENE$ is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between FLNB and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L @GENE$ proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0
"The four other variants (@GENE$ p.Q2924H, CELSR1 @VARIANT$ and @GENE$ @VARIANT$) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,CELSR1;7665,SCRIB;44228,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1.",4470809,TBK1;22742,OPTN;11085,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (p.Gln106Arg, at 0.2%; @VARIANT$, at 0.0008%; p.Arg262Gln at 0.2%; and PROKR2 @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (@GENE$/@GENE$) heterozygous mutation.",5527354,GNRHR;350,PROKR2;16368,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"In our study, we identified four genetic variants in three genes (@GENE$-@VARIANT$, @GENE$-p.C108Y, KCNH2-p.K897T, and KCNE1-@VARIANT$).",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"These results suggest an important role of ephrin-B2 as an inducer of EphA2 endocytosis with the transmembrane binding partner, @GENE$, while its effect is weaker than that of ephrin-A1.           Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of @GENE$ with mutated pendrin. myc-pendrin A372V, L445W, Q446R, @VARIANT$ were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, @VARIANT$ and F355L was not affected.",7067772,pendrin;20132,EphA2;20929,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"The proband, who had LRP6 p.(Asn1075Ser), p.(Ser127Thr), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. The @GENE$ p.(@VARIANT$) mutation substitutes highly-conserved asparagine with serine, which is predicted to destabilize the protein structure.",8621929,WNT10A;22525,LRP6;1747,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,GJB6;4936,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX @VARIANT$).",4293318,DCTN1;3011,ANG;74385,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of @GENE$ (NM_007123), R5143C, C4870F, and @VARIANT$ with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (@GENE$) identified in SH 94-208).",4998745,USH2A;66151,ANK1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,G805A;tmVar:c|SUB|G|805|A;HGVS:c.805G>A;VariantGroup:14;CorrespondingGene:7399;RS#:587783023;CA#:270788,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and @GENE$ (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,CACNA1A;56383,GNA14;68386,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, DVL3 p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"A rare variant in @GENE$, @VARIANT$; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/@GENE$ (@VARIANT$; p.Met544Ile) pathogenic missense alteration was identified.",7696449,AMH;68060,FOG2;8008,c.428C>T;tmVar:c|SUB|C|428|T;HGVS:c.428C>T;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,c.1632G>A;tmVar:c|SUB|G|1632|A;HGVS:c.1632G>A;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"We report digenic variants in SCRIB and @GENE$ associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and @GENE$ @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Her mother with c.1339 + 3A>T in @GENE$ and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROK2;9268,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS6;10318,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Three variants in three genes were rare, including the @GENE$ gene mutation [@VARIANT$], a novel heterozygous missense variant [c.1801G > A; p.(@VARIANT$)] in the @GENE$ gene (NM_001146029), as well as a splice site variation in the PLXNA1 gene (NM_032242; MAF = 0.03 in GnomAD).",8446458,PROKR2;16368,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"Patient P0432 has a @VARIANT$ (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, @GENE$ and USH2A were not found in 666 control alleles.",3125325,MYO7A;219,USH1G;56113,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,0
"Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"In Gata4ki mice with @VARIANT$ mutation interaction of Gata4 with cofactor Fog is abrogated, and consequently animals display anomalies of testis development. Moreover, GATA4 functionally interacts with NR5A1 in Sertoli cell cultures to positively regulate the expression of @GENE$, and therefore, it has been reported that mutations in NR5A1 may cause 46,XY DSD due to lack of interaction with GATA. No gonadal involvement is mostly detected in families with @GENE$ mutations and isolated CHD, possibly because some of the variants retain some DNA-binding activity and exhibit different degrees of transcriptional activation on gonadal promoters and thus, remain able to synergize with NR5A1. In the present study, the @VARIANT$ mutation was found in a patient with a complex CHD, genital ambiguity, and persistent Mullerian ducts, which led to female gender assignment.",5893726,AMH;68060,GATA4;1551,p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463,p.Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,1
"(a, b) Compared with wild-type KCNH2, the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A @VARIANT$ mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), @GENE$ p.307_308del showed a decreasing trend in molecular weight and increasing instability. However, the prediction of theoretical pI, aliphatic index and GRAVY presented no significant differences. Compared to the Nav1.5 protein properties of wild-type SCN5A, SCN5A p.R1865H slightly increased its molecular weight and aliphatic index but reduced its instability index. Theoretical pI, aliphatic index, and GRAVY were not affected by @GENE$ p.R1865H.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"   Missense variants in the NEFH gene were detected in four patients: the @VARIANT$ variant in two cases and the R148P and P505L variants in single cases. @GENE$ encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS.",6707335,NEFH;40755,GRN;1577,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,0
"20  The identified @GENE$ (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, @GENE$ variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis.",7689793,CUX1;22551,TRIP6;37757,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,VPS13C;41188,SPTBN4;11879,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Two potential disease-causing mutations were identified: (d) @GENE$: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) LAMA3 missense mutation @VARIANT$/p.Cys520Tyr. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (ENAM and @GENE$) mutations.",6785452,ENAM;9698,LAMA3;18279,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,c.1559G>A;tmVar:c|SUB|G|1559|A;HGVS:c.1559G>A;VariantGroup:6;CorrespondingGene:3909,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; @VARIANT$, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,g.124339A>G;tmVar:g|SUB|A|124339|G;HGVS:g.124339A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"ShScb, @GENE$ or @GENE$ depleted podocytes were obtained by transduction with the respective shRNAs lentiviral particles and subsequent puromycin selection.   Human ADD3 and KAT2B, were subcloned from human full-length cDNA (ADD3: clone IMAGE: 6649991; KAT2B clone IMAGE: 30333414) into the expression vectors pLentiGIII and PLEX-MCS, respectively. An HA tag was added in frame, before the stop codon, to the C terminus of ADD3 and KAT2B. The ADD3 @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol.",5973622,ADD3;40893,KAT2B;20834,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0
"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, @GENE$, DUOXA2 and TPO).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B).",7248516,SLC26A4;20132,DUOX2;9689,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PRICKLE4;22752,FZD6;2617,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,ENG;92,VEGFR2;55639,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"The proband described by Forlani et al. was heterozygous for @GENE$ E508K and @GENE$ @VARIANT$. Both mutations are novel and whilst a different mutation, R80W, has been reported in HNF4A, further evidence to support the pathogenicity of @VARIANT$ is lacking.",4090307,HNF1A;459,HNF4A;395,R80Q;tmVar:p|SUB|R|80|Q;HGVS:p.R80Q;VariantGroup:2;CorrespondingGene:3172,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,0
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and MYO6 (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"The female CACNA1C-Q1916R mutation carriers with @GENE$-@VARIANT$ variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the @GENE$-@VARIANT$ mutation (IV-4) showed the ER ECG pattern.",5426766,SCN5A;22738,CACNA1C;55484,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A).",5887939,FZD6;2617,FAT4;14377,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected.",6707335,alsin;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be @GENE$, DFNB3, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in @GENE$ (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES.",4998745,DFNB7/11;23670,GJB2;2975,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys).",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (@VARIANT$) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD6;2617,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"On the other hand, mutant GFP-@GENE$ A115P and @VARIANT$ showed perturbed interaction with HA-@GENE$. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327,0
"In patient AVM226, we identified the compound heterozygous variants @VARIANT$ (p.Val1259Ile) and c.2966A>T (p.Gln989Leu) in DSCAM (table 2). DSCAML1 and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in @GENE$ to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,SMAD1;21196,c.3775G>A;tmVar:c|SUB|G|3775|A;HGVS:c.3775G>A;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The minimum free energy (MFE) of @GENE$ @VARIANT$ increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of @GENE$ @VARIANT$ mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"NOD2, localized at chromosome 16q21, codify for a protein that belongs to the family of intracellular NLR (NOD-like receptors), able to recognize microbial components and to stimulate an inflammatory response through the activation of @GENE$. Moreover, three @GENE$ mutations (@VARIANT$, rs2066845 and @VARIANT$) represent the main genetic factor causing susceptibility to CD.",3975370,NF-kappaB;2971,NOD2;11156,rs2066844;tmVar:rs2066844;VariantGroup:8;CorrespondingGene:64127;RS#:2066844,rs5743293;tmVar:rs5743293;VariantGroup:18;RS#:5743293,0
"Finally, as regards the USH3 patients, biallelic mutations in @GENE$ and monoallelic mutations in VLGR1 or @GENE$ were found in three patients, two patients, and one patient, respectively. One USH1 and two USH2 patients were heterozygotes for mutations in two or three USH genes, suggesting a possible digenic/oligogenic inheritance of the syndrome. In the USH2 patients, however, segregation analysis did not support digenic inheritance. Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation.",3125325,USH2A;66151,WHRN;18739,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"                  In this study, we identified nine reported gene variants, and we detected 13 novel variants: @VARIANT$(p. Ser509fs) and c.1524del A(p. Ser509fs) variants in the KAl1 gene; c.223 - 4C > A and c.306G > C(p. Arg102Ser) variant in the @GENE$ gene: c.963dup A (@VARIANT$), c.1695_1696insT(p. Lys566Ter), c.580G > T(p. Gly194Cys), c.1886 T > C(p. Val629Ala), c.2147G > T(p. Gly716Val), c.1081 + 1del, c.1974_ 1977del (p. Asn659fs), and c.75_ 78del (p. Thr26fs) variants in the @GENE$ gene; and c.875 T > C (p. Ile292Thr) variant in the SEMA3A gene.",8796337,PROK2;9268,FGFR1;69065,c.1525del A;tmVar:c|DEL|1525|A;HGVS:c.1525delA;VariantGroup:13;CorrespondingGene:3730,p. Glu322fs;tmVar:p|FS|E|322||;HGVS:p.E322fsX;VariantGroup:26;CorrespondingGene:60675,0
"Notably, the patients carrying the @VARIANT$ and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in IMP4 (OMIM 612981; rs146322628, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in @GENE$ (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and @GENE$ (OMIM 612496; @VARIANT$, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,UBR4;10804,ARHGEF19;17710,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,rs144638812;tmVar:rs144638812;VariantGroup:0;CorrespondingGene:128272;RS#:144638812,1
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, @VARIANT$, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, @VARIANT$, F191L, and A197S in Cx26 as well as F193C, S198F and G199R in @GENE$, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the Cx31 gene except for the EC2 and TM4 domains, which are main domains for deafness mutations. This correlation between location of mutations and phenotypes, together with the identification of pathological mutations associated with hearing loss in the same region of the EC2 and TM4 domains in these three connexin genes (Cx26, Cx31, and Cx32) suggested that the EC2 and TM4 domains are important to the function of the @GENE$ protein in the inner ear and plays a vital role in forming connexons in the cells of the inner ear. In the present study, we have shown that the missense @VARIANT$ and A194T mutations in GJB3 acts in a recessive manner in three unrelated Chinese patients.",2737700,Cx32;137,Cx31;7338,R165W;tmVar:p|SUB|R|165|W;HGVS:p.R165W;VariantGroup:5;CorrespondingGene:2706;RS#:376898963;CA#:180672,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 @VARIANT$ with SETX @VARIANT$ and SETX p.T14I).",4293318,SOD1;392,DCTN1;3011,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"In Family K, genotyping analysis revealed that the father transmitted the @VARIANT$/@GENE$, while the mother is heterozygous for the @GENE$/@VARIANT$ (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,1
"The loss-of-function variation in @GENE$ or @GENE$ (e.g., CACNA1C-Q1916R), which produces inadequate inward hybrid currents, is responsible for the pathopoiesis of ERS. Thus, from the mechanistic point of view, INa and ICa-L show a synergistic effect on the repolarization as two ingredients of the inward currents. In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental CACNA1C-Q1916R mutation might be partly compensated by the persistent inward tail INa produced by the SCN5A-R1193Q channel. That may be how SCN5A-@VARIANT$ plays a protective role against the detrimental phenotype induced by the CACNA1C-@VARIANT$ mutation.",5426766,SCN5A;22738,CACNA1C;55484,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a).",8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (@VARIANT$) in one patient, (2) @GENE$:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Both the aborted foetuses carried the compound heterozygous pathogenic variants, namely PKD1: @VARIANT$ and @GENE$: c.7583A > G (p.Y2528C) from each parent, and these variants were inferred to have contributed to the foetal PKD. 33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the PKD1: c.4343C > T (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (p.R559W) and PKHD1: @VARIANT$ (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).          Whole-exome sequencing revealed that the foetal PKD proband in Family 23 had compound heterozygous variants in @GENE$, which was subsequently verified through Sanger sequencing.",8256360,PKD1;250,PKHD1;16336,c.1386-2A > G;tmVar:c|SUB|A|1386-2|G;HGVS:c.1386-2A>G;VariantGroup:41;CorrespondingGene:5310,c.7942G > A;tmVar:c|SUB|G|7942|A;HGVS:c.7942G>A;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 @VARIANT$), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FAT4;14377,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0
"Statistical analysis of pro-COL1A1 colocalization with endoplasmic reticulum (ER) or trans-Golgi by confocal microscopy Genotype of cell line Manders coefficient (M2) ER (PDI) overlapping pro-COL1A1 trans-Golgi (TGN38) overlapping pro-@GENE$ Wt 0.86 (N = 19) 0.11 (N = 27) SEC23Ac.1200G>C/+ 0.79 (N = 16) 0.13 (N = 28) SEC23Ac.1200G>C/+ MAN1B1c.1000C>T/+ 0.69*** (N = 59) 0.17* (N = 150) SEC23Ac.@VARIANT$/c.1200G>C; MAN1B1c.1000C>T/@VARIANT$ 0.73*** (N = 41) 0.18** (N = 138)  To determine whether increased intracellular levels of pro-COL1A1 were due to abnormal accumulation of this protein in the Golgi of mutant cells, double immunofluorescence confocal microscopy with antibodies against pro-COL1A1 and @GENE$, an integral membrane protein in the trans-Golgi, was performed.",4853519,COL1A1;73874,TGN38;136490,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"A nonsense variant in NOS2 (NM_000625.4: @VARIANT$, p.Arg687*; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs. ATP2A3 is highly expressed in cerebellar Purkinje cells (Allen Brain Atlas) and is a member of the P-type ATPase superfamily that includes the gene (ATP1A3) causally associated with rapid-onset dystonia-Parkinsonism (@GENE$).                            GNA14 and HS1BP3 variants in pedigree with BSP+ and Parkinsonism A novel @GENE$ nonsynonymous SNV (c.94C>A [NM_022460.3], @VARIANT$ [NP_071905.3]) was found in a father and son with severe BSP+ (Family 10043; Figure 6; Tables 1, 5, 8 and S2; Data S1).",6081235,DYT12;113729,HS1BP3;10980,c.2059C>T;tmVar:c|SUB|C|2059|T;HGVS:c.2059C>T;VariantGroup:11;RS#:200336122,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, p. R434*). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .   In vitro evaluation of a similarly truncated DUOX1 isoenzyme comprising amino acids 1 to 593 alone abolished H2O2-generating activity. Moreover, similar truncations in the highly homologous DUOX2 [@VARIANT$, p.R701*, p.(G418fsX482);(IVS19-2A>C), p.S965fsX994] are associated with CH or severely impaired H2O2-generating activity in vitro.",5587079,DUOX1;68136,DUOX1 and -2;53905;50506,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p.Q686*;tmVar:p|SUB|Q|686|*;HGVS:p.Q686*;VariantGroup:20;CorrespondingGene:50506,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB2;2975,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
Representative western blot and bar graph showing expression levels of @GENE$ (A) and @GENE$ (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts.,4853519,SEC23A;4642,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, @VARIANT$), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,REEP4;11888,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,0
"  Digenic inheritances of GJB2/@GENE$ and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in @GENE$, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,MITF;4892,GJB2;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Moreover, the presence of other variants (KCNQ1-@VARIANT$, KCNH2-p.K897T, and @GENE$-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. On the contrary, in the mother, some other factors, including unknown genetic modifiers, could counteract the functional impairment of mutant channels, thereby protecting the asymptomatic @GENE$-@VARIANT$ mutation-positive subject from arrhythmia susceptibility.",5578023,KCNE1;3753,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 3;7338,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,ENG;92,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX @VARIANT$ and SETX p.T14I).",4293318,VAPB;36163,ANG;74385,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ @VARIANT$ (p.M400I) and @GENE$ @VARIANT$ (p.R334C), associated with congenital birth defects in two patients from a consanguineous family.",4853519,SEC23A;4642,MAN1B1;5230,c.1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1
"We identified four genetic variants (KCNQ1-p.R583H, @GENE$-p.C108Y, KCNH2-p.K897T, and @GENE$-@VARIANT$) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNH2;201,KCNE1;3753,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. We found that mutations in the two genes segregated in the family and that the unaffected parents were healthy and carried heterozygous mutations in both SEC23A and MAN1B1, consistent with an autosomal-recessive mode of inheritance. We also identified heterozygous mutation in SEC23A in an unaffected sibling of tall stature and normal intelligence. Fibroblasts were isolated and used to characterize cellular abnormalities associated with these mutations and to confirm contribution of both mutations to abnormal protein transport. We propose that homozygosity for both of these mutations in @GENE$ and @GENE$ explains a subset of phenotypic abnormalities found in the affected boys.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in IMP4 (OMIM 612981; rs146322628, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in UBR4 (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and ARHGEF19 (OMIM 612496; @VARIANT$, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus. To date, @GENE$ and @GENE$ have not been linked to a medical disorder.",6081235,IMP4;68891,ARHGEF19;17710,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,rs144638812;tmVar:rs144638812;VariantGroup:0;CorrespondingGene:128272;RS#:144638812,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Rare CTRC genotypes contributed to the development of ICP in 4.3% of cases  CTRC has conventionally been regarded as being the least important gene in terms of a genetic predisposition to chronic pancreatitis, as compared with PRSS1 and @GENE$. This view received further support from two recent developments. First, some of the CTRC variants characterized by a complete or virtually complete functional loss of the affected alleles, exemplified by p.K247_R254del and p. G217S, have been reported in unrelated healthy controls. Second, whereas a heterozygous CTRC whole gene deletion was found in trans with other genetic predisposing alleles in two subjects with familial chronic pancreatitis, a different homozygous CTRC whole gene deletion was identified in a patient with asymptomatic ICP. Employing the functionally null CTRC allele, p.K247_@VARIANT$, which increases the risk of ICP 6.4-fold, as a reference (N.B. the heterozygous SPINK1 @VARIANT$ allele confers a >10-fold increased risk), any loss-of-function variants in the @GENE$ gene may at most be interpreted as disease-predisposing.",3738529,SPINK1;68300,CTRC;21422,R254del;tmVar:p|DEL|254|R;HGVS:p.254delR;VariantGroup:21;CorrespondingGene:11330,p. N34S;tmVar:p|SUB|N|34|S;HGVS:p.N34S;VariantGroup:7;CorrespondingGene:6690;RS#:17107315;CA#:123440,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ @VARIANT$ and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-@GENE$ @VARIANT$, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,1
"Pedigree and sequence chromatograms of the patient with the @VARIANT$ in @GENE$ and c.158-1G>A in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in MYO7A. Another variation, @VARIANT$ in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,1
"(b) The changed site of SCN5A gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant DISCUSSION In our study, the proband with overlapped phenotypes of young early-onset LQTS and sinoatrial node dysfunction was first demonstrated to carry with the digenic heterozygous and pathogenic mutations of @GENE$ p.307_308del and @GENE$ @VARIANT$. KCNH2 @VARIANT$ induced a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized, which thus mainly caused LQTS.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in EHMT1 and a missense variant @VARIANT$ (p.Leu593Val) in @GENE$. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases.,7463850,SLC9A6;55971,EHMT1;11698,p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"(b) The changed site of SCN5A gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant DISCUSSION In our study, the proband with overlapped phenotypes of young early-onset LQTS and sinoatrial node dysfunction was first demonstrated to carry with the digenic heterozygous and pathogenic mutations of KCNH2 @VARIANT$ and @GENE$ @VARIANT$. @GENE$ p.307_308del induced a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized, which thus mainly caused LQTS.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of @GENE$ and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"Including the validation cohort, p.K530X, IVS28+1G>T, p.R885Q, p.L1343F, and @VARIANT$ were also common in Xinjiang DH patients. TG mutations were the second most prevalent genetic alterations in DH: five different heterozygous variants were found in 5/21 patients (23.8%), and these often cooccurred with DUOX2 or @GENE$ mutations. DUOX2 and TG mutation locations varied in the corresponding proteins (Figure 2). Additionally, three DUOXA2 variants were found in 3/21 patients (14%), and a known heterozygous variant in SLC26A4 was found in one patient. No mutations in SLC5A5, @GENE$, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: @VARIANT$ (p.Y138X) in one patient.",6098846,DUOXA2;57037,TPO;461,p.R683L;tmVar:p|SUB|R|683|L;HGVS:p.R683L;VariantGroup:11;CorrespondingGene:50506;RS#:8028305;CA#:7538397,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, @VARIANT$, p.S82T, p. A85P, p.L86F, p.F112S, @VARIANT$, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,FOXC1;20373,PITX2;55454,p.P79T;tmVar:p|SUB|P|79|T;HGVS:p.P79T;VariantGroup:108;CorrespondingGene:6012,p.R127L;tmVar:p|SUB|R|127|L;HGVS:p.R127L;VariantGroup:19;CorrespondingGene:2296;RS#:1085307884,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the @GENE$ missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"C. Sanger sequencing confirmation of heterozygous @GENE$ variant c.739C>T (@VARIANT$) in V.5, and @GENE$ variant @VARIANT$ in VI.3.",6057824,COL4A1;20437,PKD2;20104,p.Gln247*;tmVar:p|SUB|Q|247|*;HGVS:p.Q247*;VariantGroup:0;CorrespondingGene:1282,c.715_718dupTACG;tmVar:c|DUP|715_718|TACG|;HGVS:c.715_718dupTACG;VariantGroup:2;CorrespondingGene:5311,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%). No significant change was observed with HA-TEK G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2).,5953556,TEK;397,CYP1B1;68035,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Three known rare SPINK1 mutations, p. @GENE$ , @VARIANT$ and @VARIANT$, each of which was found once in the current study, were deemed to be disease causing by virtue of their predicted functional consequences. These three mutations (and other presumed or experimentally demonstrated loss-of-function mutations) in the @GENE$ gene were almost invariably found in patients rather than controls.",3738529,M1?;20189,SPINK1;68300,IVS2+1G > A;tmVar:c|SUB|G|IVS2+1|A;HGVS:c.IVS2+1G>A;VariantGroup:23;CorrespondingGene:1128,IVS3+2T>C;tmVar:c|SUB|T|IVS3+2|C;HGVS:c.IVS3+2T>C;VariantGroup:15;CorrespondingGene:6690;RS#:148954387;CA#:345639,0
"This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare glycine decarboxylase (@GENE$) @VARIANT$ missense variant, possibly indicating a compromised FOCM in this patient.",5887939,MTHFR;4349,GLDC;141,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332,1
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT5;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"The p.Ala349Thr (@VARIANT$) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of @GENE$ were detected. These mutations were not found in his father's genome, but because his mother's DNA sample was unavailable, the origin of the mutant alleles was not clear (Fig. 2F).     All novel mutations that were identified in this study were not found in the normal controls. Protein structure analysis The results of protein structure analyses of WNT10A are shown in Figure 3. @VARIANT$ and G213 are conserved residues through these organisms and located on conserved 2D fragments.",3842385,EDA;1896,WNT10A;22525,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555,0
"The genotypes of @GENE$ (NM_001257180.2: @VARIANT$, p.His596Arg) and PDGFRB (NM_002609.4: @VARIANT$, p.Arg106Pro) for available individuals are shown. Regarding SLC20A2, A/G = heterozygous mutation carrier, and A/A = wild type; regarding @GENE$, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"The presence of concomitant mutations, such as the @GENE$ T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/@GENE$ mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"In AS patient IID27, the two mutations in @GENE$ and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation @VARIANT$ in COL4A5, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a).",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,DCTN1;3011,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"NGS reads indicated the identification of homozygous missense pathogenic variants @VARIANT$ (p.R758C) and @VARIANT$ (R284C) in ANO5 and SGCA genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in @GENE$ gene and one pathogenic variant in COL6A2 gene indicating multiple gene contributions for an unusual presentation. His mother, a 40-year-old female with one pathogenic variant each in ANO5 and COL6A2 shows unspecified myopathy with elevated creatine phosphokinase (CPK).         Deep intronic variant in @GENE$ gene Recently, we characterized a deep intronic mRNA splice-altering pathogenic variant c.4886 + 1249G>T in DYSF gene that inserts a novel 177 bp pseudoexon at the exon 44-45 junction.",6292381,ANO5;100071,DYSF;20748,c.2272C>T;tmVar:c|SUB|C|2272|T;HGVS:c.2272C>T;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, @VARIANT$ and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of NOD2 protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the @VARIANT$ substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,c.475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and @GENE$ @VARIANT$ mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for REEP4 @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates                @GENE$ missense variant A TOR2A nonsynonymous SNV (@VARIANT$ [NM_130459.3], p.Arg190Cys [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,BSP+;3644,TOR2A;25260,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"As negative control, no interaction was detected between the GFP tag and HA-@GENE$ proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished. GFP-@GENE$ R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2).",5953556,TEK;397,CYP1B1;68035,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and @GENE$.       3.5. Predicted Structural Alterations and Pathogenicity of LRP6 Missense Mutations Computational prediction of the structural impact for the five LRP6 missense mutations on protein stability demonstrated that @VARIANT$, @VARIANT$, and p.Asn1075Ser were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively.",8621929,LRP6;1747,WNT10A;22525,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"The @VARIANT$ variant alters an amino acid that is highly conserved among vertebrates (Figure 5). Another candidate variant in @GENE$ (@VARIANT$) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of MYH13 is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: c.2059C>T, p.Arg687*; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs.",6081235,MYH13;55780,NOS2;55473,Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,rs7807826;tmVar:rs7807826;VariantGroup:17;RS#:7807826,0
"The latter individuals were also carriers of the @GENE$ nonsense mutation p.R1141X. It should be noted that the mother and her twin sister were heterozygous for one of the @GENE$ missense mutation @VARIANT$ and one ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings.",2900916,ABCC6;55559,GGCX;639,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [@VARIANT$]) in TIMP3 were identified (online supplementary table S2).",6161649,BMP;55955,ENG;92,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,DCTN1;3011,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 3;7338,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2).,5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB3;7338,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, c.1070A > G (@VARIANT$) and SQSTM1, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis.         We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: 179260153C/T, refSNP ID rs4935; Chr5: 179260213G/A, rs4797; Chr5: 179264731T/C, rs10277; Ch5: @VARIANT$, rs1065154 ]. On the basis of our available sequencing data, we attempted to infer the haplotype of the @GENE$ mutation for each family.",5868303,TIA1;20692,SQSTM1;31202,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,179264915G/T;tmVar:c|SUB|G|179264915|T;HGVS:c.179264915G>T;VariantGroup:2;CorrespondingGene:8878;RS#:1065154,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Similarly, the @GENE$-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant @VARIANT$ of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in @GENE$, a causative gene of IHH.",8152424,CCDC88C;18903,CHD7;19067,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
"This hypothesis was further supported when a patient with Kallmann syndrome was discovered to carry the same PROKR2 heterozygous mutation as our proband, @VARIANT$, in combination with a second heterozygous mutation in @GENE$, c.1810G>A;@VARIANT$ (NM_023110.2), thereby providing evidence for a digenic basis for the syndrome. Prokineticin 2 and @GENE$ are both expressed in the hypothalamus and pituitary, and reduced expression or activity of PROKR2 is implicated in both Kallmann syndrome and PSIS, perhaps because of the important role this signaling pathway plays in endocrine angiogenesis and neuronal migration in this region of the central nervous system.",5505202,FGFR1;69065,PROKR2;16368,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.A604T;tmVar:p|SUB|A|604|T;HGVS:p.A604T;VariantGroup:5;CorrespondingGene:2260;RS#:1412996644,0
"Further molecular studies are needed to prove the deleterious character of the @GENE$ Lys205del variant. Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in @GENE$, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,PROKR2;16368,DUSP6;55621,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Nevertheless, in vitro studies demonstrated that the @GENE$-@VARIANT$ variant causes only a mild reduction of the delayed rectifier K+ currents. Therefore, G38S could be a genetic modifier, but the evidence available does not suggest it has an overt effect on the function of the KCNQ1 and KCNH2 channels. Given the complexity of the LQTS-related genetic background in our family, we functionally characterized only KCNH2-p.C108Y and KCNQ1-p.R583H. Our data demonstrate that the activity of @GENE$-@VARIANT$ was significantly lower than that of the wild type.",5578023,KCNE1;3753,KCNH2;201,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the @GENE$ gene (LQT6).",6610752,KCNH2;201,KCNE2;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Among others, a known missense variant was detected in the @GENE$ gene (@VARIANT$), which is associated with mitochondrial disorders and Charcot-Marie-Tooth disease, and two variants of conflicting significance in the @GENE$ gene (@VARIANT$ and R166C), which is associated with autosomal recessive adult-type polyglucosan body disease (Online Mendelian Inheritance in Man).",6707335,GJB1;137,GBE1;129,R230C;tmVar:p|SUB|R|230|C;HGVS:p.R230C;VariantGroup:28;CorrespondingGene:2705;RS#:587781246;CA#:270921,H398R;tmVar:p|SUB|H|398|R;HGVS:p.H398R;VariantGroup:18;CorrespondingGene:2632;RS#:755004170;CA#:2499769,0
"Moderate iodine deficiency in association with double heterozygosity for DUOX1 and @GENE$ mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (@VARIANT$), inherited digenically with a homozygous DUOX2 nonsense mutation (@VARIANT$, p. R434*).",5587079,DUOX2;9689,DUOX1;68136,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,0
"Repeat expansions in chromosome 9 open reading frame 72 (@GENE$) and mutations in progranulin (@GENE$) are the major known genetic causes of FTLD-TDP; however, the genetic etiology in the majority of FTLD-TDP remains unexplained. In this study, we performed whole-genome sequencing in 104 pathologically confirmed FTLD-TDP patients from the Mayo Clinic brain bank negative for C9ORF72 and GRN mutations and report on the contribution of rare single nucleotide and copy-number variants in 21 known neurodegenerative disease genes. Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1.",4470809,C9ORF72;10137,GRN;1577,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,GJB6;4936,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"In the subject III.1, the variant, carried in the heterozygous status, is the @VARIANT$; p.Glu290*, in the @GENE$ (CGK) gene; the III.2 subject carried the c.872 C > G; @VARIANT$, in the @GENE$ gene.",8306687,glucokinase;55440,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"All these variants were frequent, with a MAF ranging from 0.2 to 0.6 according to the GnomAD database, except for the missense variant [c.2803C > T; p.(@VARIANT$)] in the @GENE$ gene (MAF = 0.06) (Supplementary Table 2). This variant was absent in the in-house control database. Despite being predicted as benign by Varsome, this variant [p.(Arg935Trp)] was involved in the second most important pathogenic combinations (15%; 13 genes) in HH1, after the PROKR2 gene variant [p.(@VARIANT$)]. On the other hand, when the CCDC141 variant was at a heterozygous state, prediction by ORVAL yielded only two pathogenic digenic combinations with PROKR2 and @GENE$ variants in HH1F and HH1P cases (Figure 4).",8446458,CCDC141;52149,DUSP6;55621,Arg935Trp;tmVar:p|SUB|R|935|W;HGVS:p.R935W;VariantGroup:4;CorrespondingGene:285025;RS#:17362588,Pro290Ser;tmVar:p|SUB|P|290|S;HGVS:p.P290S;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257,0
"        Molecular Data All three probands carry two heterozygous variants: SQSTM1, @VARIANT$ (p.Pro392Leu), and TIA1, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and @GENE$ variants have been reported in multiple databases.",5868303,TIA1;20692,SQSTM1;31202,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
" @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,TOR2A;25260,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Since @VARIANT$ was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease. This NELF deletion was associated with exon 10 skipping, but was not sufficient to cause KS alone. Therefore, no human @GENE$ mutations, supported in vitro, and without mutations in a second gene, have been reported to cause IHH/KS. In the present study, 3/168 (1.8%) of IHH/KS patients had NELF mutations demonstrating impaired function in vitro, which is similar to GNRHR and greater than KISS1R mutations in nIHH patients. To exclude digenic disease, sequencing of 11 additional genes (CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, KAL1, @GENE$, GNRH1, and KISS1R) was performed.",3888818,NELF;10648,GNRHR;350,Thr478;tmVar:p|Allele|T|478;VariantGroup:0;CorrespondingGene:26012;RS#:121918340,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (rs143445685), @GENE$ (@VARIANT$), and @GENE$ (@VARIANT$) genes.",6180278,CAPN3;52,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Moreover, given the complex association of LQTS mutants in the individuals of the family and the potential causative role of each mutation, and also based on in silico analysis and on evidence from previous studies, we focused on the in vitro functional characterization of the @GENE$-@VARIANT$ and @GENE$-p.C108Y variants. 2.3. Functional Consequences of the KCNQ1-p.R583H and KCNH2-p.C108Y Variants To investigate the functional consequences of KCNQ1-p.R583H and KCNH2-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (@VARIANT$) and the @GENE$ gene (@VARIANT$) yet did not display any cutaneous findings are not clear.,2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,1
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), EPHA2: @VARIANT$ (p.G355R) and @GENE$: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"In subject 10035, a deleterious variant within the @GENE$ (Chr2) locus was identified in @GENE$ (OMIM 612981; rs146322628, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in UBR4 (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and ARHGEF19 (OMIM 612496; @VARIANT$, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,DYT21;100885773,IMP4;68891,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,rs144638812;tmVar:rs144638812;VariantGroup:0;CorrespondingGene:128272;RS#:144638812,0
"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; @VARIANT$); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD @VARIANT$ (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of @GENE$ and @GENE$ genes are closely related to LQTS.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.E1028V;tmVar:p|SUB|E|1028|V;HGVS:p.E1028V;VariantGroup:5;CorrespondingGene:3757,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
The KCNQ1-@VARIANT$ variant was previously reported to be associated with LQTS; KCNH2-p.C108Y is a novel variant; and @GENE$-p.K897T and @GENE$-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels.,5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Proband 17 inherited @GENE$ @VARIANT$ and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,CHD7;19067,CDON;22996,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"For a more comprehensive review of the role of @GENE$ in CHD we refer to Ref..       By contrast, the few GATA4 missense mutations found in 46,XY DSD individuals with or without CHD are all located in the N-terminal zinc finger domain, which is responsible for DNA binding and interaction with cofactors. Functional characterization of GATA4 variants with respect to the 46,XY DSD phenotype has only been performed for the @VARIANT$ mutation so far. In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the @GENE$ promoter, and failed to bind cofactor FOG2. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation p.Cys238Arg, but no effect on transactivation activity on the CYP17 promoter for GATA4 variants p.Pro226Leu and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only @VARIANT$ and Cys238 are close to Zn binding sites.",5893726,GATA4;1551,AMH;68060,p.Gly221Arg;tmVar:p|SUB|G|221|R;HGVS:p.G221R;VariantGroup:4;CorrespondingGene:2626;RS#:398122402(Expired),Gly221;tmVar:p|Allele|G|221;VariantGroup:4;RS#:398122402(Expired),0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and @VARIANT$; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,gap junction protein beta 6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"This mutation changes codon 554 from arginine to a stop codon (@VARIANT$; @VARIANT$) and has been previously reported. The mother did not carry this luteinizing hormone/choriogonadotropin receptor (LHCGR) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, @GENE$, and @GENE$ promoters.",5893726,SRY;48168,CYP17;73875,c.1160C>T;tmVar:c|SUB|C|1160|T;HGVS:c.1160C>T;VariantGroup:1;CorrespondingGene:2626;RS#:368991748;CA#:172121374,p.Arg554Stop;tmVar:p|SUB|R|554|X;HGVS:p.R554X;VariantGroup:1;CorrespondingGene:3973;RS#:368991748,0
"21  Additional gene reportedly linked to tumorigenesis include @GENE$, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: @VARIANT$, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,RYR3;68151,TRIP6;37757,c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"   The substitutions of Leu117 to Phe (L117F), @VARIANT$ (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,Ser166 to Asn;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,TARDBP;7221,ANG;74385,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,0
Merged images showing pro-@GENE$ colocalization with TGN38 in wild-type (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ MAN1B1R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ @GENE$R334C/@VARIANT$ double-homozygous (L) fibroblasts.,4853519,COL1A1;73874,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,0
"Moreover, the MAF of KCNQ1-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and @GENE$-p.G38S were much larger (0.187 and 0.352, respectively). KCNH2-p.C108Y is not reported in the ExAC database.                 All the known variants identified in the family were reported to have functional relevance for cardiac electrophysiology and, therefore, could potentially contribute to the pathogenesis of the LQTS phenotype in the family. As neither a variant nor a combination of variants clearly segregated with the LQTS phenotype, it was not possible to assign a priori pathogenicity to any of these variants without performing additional (e.g., functional) studies. Moreover, given the complex association of LQTS mutants in the individuals of the family and the potential causative role of each mutation, and also based on in silico analysis and on evidence from previous studies, we focused on the in vitro functional characterization of the @GENE$-p.R583H and KCNH2-@VARIANT$ variants.",5578023,KCNE1;3753,KCNQ1;85014,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and @GENE$ and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated @GENE$ mutation (c.1403 C > T; @VARIANT$) and a novel, potentially pathogenic missense SOS1 variant (c.1018 C > T; @VARIANT$) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,neurofibromatosis 1;226,PTPN11;2122,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0
"(A) In addition to @VARIANT$ in GJB2, the de novo variant of @GENE$, p.R341C was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus. (C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates.",4998745,MITF;4892,GJB6;4936,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and TAF15 @VARIANT$ with @GENE$ p.I2547T and SETX p.T14I).,4293318,ANG;74385,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"However, it was hard to determine whether the coexisting interactions of @GENE$ p.307_308del and SCN5A @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while @GENE$ mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 @VARIANT$ and SCN5A p.R1865H by WES and predisposing genes analyses.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"All of them had confirmed hypogonadotropic hypogonadism and anosmia or hyposmia, and some already harbored a mutation in one of the five KS genes we had previously analyzed, specifically, in KAL1 (13 patients), FGFR1 (30 patients), FGF8 (3 patients), @GENE$ (30 patients), or PROK2 (12 patients). Nonsynonymous mutations in SEMA3A were found in 24 patients (20 males and 4 females), all in heterozygous state (Table 1). They consist of a frameshifting deletion of 14 nucleotides (c.del1613_1626; @VARIANT$), and seven different missense mutations (p.R66W, p.N153S, p.I400V, p.V435I, p.T688A, p.R730Q, p.R733H) that affect evolutionarily conserved aminoacid residues located in different domains of the protein (Figure 3). In addition, the p.R730Q and @VARIANT$ mutations, which both remove basic residues in the C-terminal basic motif of @GENE$, are predicted to affect in vivo proteolytic processing by furin-like endoproteases at residue R734.",3426548,PROKR2;16368,Sema3A;31358,p.D538fsX31;tmVar:p|FS|D|538||31;HGVS:p.D538fsX31;VariantGroup:12;CorrespondingGene:2260,p.R733H;tmVar:p|SUB|R|733|H;HGVS:p.R733H;VariantGroup:6;CorrespondingGene:10371;RS#:318240753;CA#:220075,0
"Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"A total of 2 novel variants, p.S309P and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and p.K618 were novel. @VARIANT$ is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and p.R528S and p.K618* are located in the cytoplasmic loops (Fig. S3C). Patients with GIS had a higher tendency to be affected with mutations than patients with TD [25/32 (78%) vs. 6/11 (54%), Fig. 2]. Variants in TG, @GENE$, DUOXA2, @GENE$ and PROP1 genes were found exclusively in patients with GIS, and 1 variant in TRHR was found in patients with TD.",7248516,TSHR;315,SLC5A5;37311,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 3;7338,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In the other three families, the variants were located in @GENE$-@GENE$, ABCC8-SARS2, and TBX4-SMAD1. Three of these families were classified as IPAH and the other two as PAH-CHD.  In all consanguineous individuals with a clinical diagnosis of PVOD, we found the known Spanish founder missense pathogenic variant in EIF2AK4:NM_001013703.3:@VARIANT$(@VARIANT$) in a homozygous state.",7650688,ABCC8;68048,NOTCH3;376,c.3344C>T;tmVar:c|SUB|C|3344|T;HGVS:c.3344C>T;VariantGroup:21;CorrespondingGene:6833;RS#:774906916;CA#:7474312,p.Pro1115Leu;tmVar:p|SUB|P|1115|L;HGVS:p.P1115L;VariantGroup:21;CorrespondingGene:440275;RS#:774906916;CA#:7474312,0
"This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,BMP;55955,SCUBE2;36383,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, @GENE$ @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,PTK7;43672,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,CELSR1;7665,FZD6;2617,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ @VARIANT$ to immunoprecipitate HA-TEK @VARIANT$ and HA-@GENE$ Q214P, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"(A) The @GENE$ mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and WNT10A mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,TARDBP;7221,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (c.229C>T; @VARIANT$) and d) the c.238-241delATTG (p.I80Gfs*13) in S100A13. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.    Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, @VARIANT$ in ISG20L2, rs143224912 in SETDB1 and rs138355706 in S100A3, and one novel variant in @GENE$, were identified. The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts.",6637284,S100A13;7523,SETDB1;32157,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,rs3795737;tmVar:rs3795737;VariantGroup:5;CorrespondingGene:81875;RS#:3795737,0
"He also had a KAL1 deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with @GENE$/KAL1 mutations had no mutations in CHD7, @GENE$, FGFR1, PROK2, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,NELF;10648,FGF8;7715,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. The authors raised the possibility of a digenic myopathy, which up to date has not been proven.     Herein, we describe the clinical and pathological phenotype of three unrelated probands harboring the combined heterozygous TIA1 and @GENE$ variants in the setting of MRV or myofibrillar pathology, providing evidence that co-occurrence of these variants are associated with late-onset myopathy.",5868303,TIA1;20692,SQSTM1;31202,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of @GENE$ were extracted, which revealed one common variant (@VARIANT$) in intron 1 with a MAF of 0.3 according to GnomAD.",8446458,SEMA7A;2678,PROKR2;16368,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,c.-9 + 342A > G;tmVar:c|SUB|A|-9+342|G;HGVS:c.-9+342A>G;VariantGroup:3;CorrespondingGene:128674;RS#:7351709,0
"However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on @GENE$ p.307_308del and @GENE$ @VARIANT$ by WES and predisposing genes analyses.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: @VARIANT$ (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and @GENE$: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,1
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB6;4936,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Among the 8 novel variants, 4 were classified as P (p.C176R and @VARIANT$ in @GENE$, p.T803fs in DUOX2) or LP (@VARIANT$ in @GENE$), the other were classified as VUS.",7248516,TSHR;315,DUOX2;9689,p.K618*;tmVar:p|SUB|K|618|*;HGVS:p.K618*;VariantGroup:4;CorrespondingGene:7253,p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506,0
"(A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and @GENE$ mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in @GENE$ to block its activity in BMP/TGF-beta signalling.",6161649,MAP4K4;7442,SMAD1;21196,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and @GENE$ and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated @GENE$ mutation (@VARIANT$; p.T468M) and a novel, potentially pathogenic missense SOS1 variant (c.1018 C > T; @VARIANT$) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,neurofibromatosis 1;226,PTPN11;2122,c.1403 C > T;tmVar:c|SUB|C|1403|T;HGVS:c.1403C>T;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0
"(A) Segregation of the KCNQ1-@VARIANT$, KCNH2-p.C108Y, @GENE$-p.K897T, and @GENE$-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Quantification of cells with dilated endoplasmic reticulum (ER) and COPII vesicles associated with Golgi by transmission electron microscopy Genotype of cell line Cells with dilated ER (%) Cells with Golgi-associated vesicles (%) Wt (N = 414) 2 (0.5) 309 (75) SEC23A@VARIANT$/+ (N = 83) 83 (100***) 9 (11***) SEC23Ac.1200G>C/+ MAN1B1c.1000C>T/+ (N = 190) 190 (100***) 3 (1.6***) SEC23Ac.1200G>C/c.1200G>C; MAN1B1c.1000C>T/@VARIANT$ (N = 328) 328 (100***) 2 (0.6***)  Increased Intracellular and Secreted Pro-COL1A1 in Fibroblasts with Homozygous Mutations in Both @GENE$ and @GENE$ in the Presence of l-Ascorbic Acid SEC23A is required for normal transport of pro-COL1A1, a major extracellular matrix component of bone.",4853519,SEC23A;4642,MAN1B1;5230,c.1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"@GENE$ @VARIANT$ and @GENE$ p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to OPTN in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (CSF1R), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (@GENE$).       CNV analysis of the 21 neurodegenerative disease genes using Ingenuity Variant Analysis software further identified one patient with a partial deletion of OPTN (NM_001008211.1:@VARIANT$; p.Gly538Glufs27).",4470809,TBK1;22742,FUS;2521,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,c.1243-740_1612+1292delins25;tmVar:c|INDEL|1243-740_1612+1292|25;HGVS:c.1243-740_1612+1292delins25;VariantGroup:37;CorrespondingGene:10133,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
The siblings we describe with the @GENE$ P291fsinsC and @GENE$ @VARIANT$ mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic. The HNF1A P291fsinsC (@VARIANT$) mutation is the most common of all MODY mutations: it results in a frameshift and premature termination codon.,4090307,HNF1A;459,HNF4A;395,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,0
"All three novel NR5A1 variants had significantly reduced activity on the @GENE$ reporter compared to WT (Figure 2A). These results were confirmed for the His24Leu and @VARIANT$ variants when using the reporters for CYP11A1 and HSD17B3 (Figure 2B,C). In contrast, variant @VARIANT$ did not change the reporter activities of CYP11A1 and HSD17B3 (Figure 2B,C). Expression of NR5A1 variants was assessed by Western blot in our cell model. As shown in Figure 2D, SF1 protein expression was similar for all studied NR5A1 variants. 3. Discussion Patients harboring @GENE$ variants manifest with extremely broad phenotypes, ranging from normal sex development to complete sex reversal.",7696449,CYP17A1;73875,NR5A1;3638,Cys30Ser;tmVar:p|SUB|C|30|S;HGVS:p.C30S;VariantGroup:5;CorrespondingGene:6662;RS#:1003847603;CA#:293780979,Cys301Tyr;tmVar:p|SUB|C|301|Y;HGVS:p.C301Y;VariantGroup:2;CorrespondingGene:6736,0
"The WNT10A mutation (@VARIANT$, rs148714379), while being rare (MAF = 0.0003), was categorized as a benign variant (PolyPhen-2 score = 0.087). Segregation analysis showed that the father carried the two LRP6 variants, while the mother and the younger sister were both heterozygotes for the WNT10A mutation. These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in LRP6 and @GENE$.       3.5. Predicted Structural Alterations and Pathogenicity of LRP6 Missense Mutations Computational prediction of the structural impact for the five @GENE$ missense mutations on protein stability demonstrated that p.Met168Arg, p.Ala754Pro, and p.Asn1075Ser were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively. Particularly, @VARIANT$ and p.Ala754Pro were highly destabilizing, as their DeltaDeltaGs were higher than 1.00 kcal mol-1.",8621929,WNT10A;22525,LRP6;1747,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,0
"In addition, we found an elevated frequency (8%) of heterozygous and rare PITX2 variants in the group of CG cases who were known to carry @GENE$ glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and PITX2: @VARIANT$, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and @VARIANT$; @GENE$: p.(P179T)).",6338360,CYP1B1;68035,PITX2;55454,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"Compound heterozygous variants in DSCAML1, DSCAM and @GENE$ were retained. In two unrelated patients, AVM106 and AVM285, identical compound heterozygous variants were identified in DSCAML1: c.5783G>A (@VARIANT$) and c.4574G>A (p.Arg1525His), each inherited from heterozygous carrier parents (table 2). Both variants were reported in ExAC with an allele frequency <0.001, and they were predicted in silico to be highly deleterious (GERP++>4 and CADD>30 for both). In patient AVM226, we identified the compound heterozygous variants c.3775G>A (p.Val1259Ile) and c.2966A>T (@VARIANT$) in @GENE$ (table 2).",6161649,PTPN13;7909,DSCAM;74393,p.Arg1928His;tmVar:p|SUB|R|1928|H;HGVS:p.R1928H;VariantGroup:5;CorrespondingGene:57453;RS#:1212415588,p.Gln989Leu;tmVar:p|SUB|Q|989|L;HGVS:p.Q989L;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"To the best of our knowledge, two of the identified variants (@GENE$: @VARIANT$, p.(H395N); and PITX2: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent @GENE$ variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and p.(H395N); PITX2: p.(P179T)).",6338360,FOXC2;21091,PITX2;55454,c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,0
"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ @VARIANT$, rs761703397), and 0.0284 (@GENE$ @VARIANT$, rs147680216) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (@VARIANT$), @GENE$ (@VARIANT$), CAPN3 (rs138172448), and DES (rs144901249) genes.",6180278,COL6A3;37917,RYR1;68069,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The DNA sequencing chromatograms from the proband show two @GENE$ and one WNT10A heterozygous mutations. While both LRP6 variants, p.(Ser127Thr) and p.(@VARIANT$), were inherited from her father, the @GENE$ mutation, @VARIANT$ was maternally derived.",8621929,LRP6;1747,WNT10A;22525,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for @GENE$ and KCNH2 mutations. KCNH2 p.307_308del and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type @GENE$ (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b).",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Apart from the repeat expansion, a rare missense variant of uncertain significance (@VARIANT$) was also detected in the C9orf72 gene. According to the NGS results, the most frequently mutated genes were NEK1 (6/107, 5.6%), NEFH, SQSTM1 (4/107, 3.7%), KIF5A, SPG11 (3/107, 2.8%), @GENE$, CCNF, @GENE$, MATR3, TBK1, and UBQLN2 (2/107, 1.9%). Furthermore, potentially relevant variants were found in the GRN and SIGMAR1 genes in single patients ( Table 2 ). Because of the relatively high prevalence of the NEK1 R261H variant in our patient cohort (5/107), we further evaluated 186 additional healthy controls (total 370) for this variant. @VARIANT$ was identified in 5/107 (4.67%) patients and 4/370 (1.08%) controls, showing an enrichment in patients (MAF: 0.0234 vs 0.0054; p = 0.0162).",6707335,ALS2;23264,FUS;2521,R431Q;tmVar:p|SUB|R|431|Q;HGVS:p.R431Q;VariantGroup:19;CorrespondingGene:203228;RS#:753335393;CA#:5017643,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"It should be noted that the mother and her twin sister were heterozygous for one of the @GENE$ missense mutation @VARIANT$ and one @GENE$ nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,1
"(A) Patient with homozygous variants in both @GENE$ and @GENE$ genes. NGS reads indicated the identification of homozygous missense pathogenic variants @VARIANT$ (p.R758C) and @VARIANT$ (R284C) in ANO5 and SGCA genes, respectively.",6292381,ANO5;100071,SGCA;9,c.2272C>T;tmVar:c|SUB|C|2272|T;HGVS:c.2272C>T;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"In Family F, the @GENE$/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/@GENE$, while the mother is heterozygous for the GJB2/299-300delAT (Fig. 1k).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We identified four genetic variants (@GENE$-p.R583H, @GENE$-p.C108Y, KCNH2-@VARIANT$, and KCNE1-@VARIANT$) in an LQTS family.",5578023,KCNQ1;85014,KCNH2;201,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(@VARIANT$). Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(Ser872Gly) variant in PKD1, while only one fetus inherited the p.(Arg872Gly) @GENE$ variant. The analysis of @GENE$ performed on the first fetus showed no mutations.",7224062,PKD2;20104,PKHD1;16336,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (rs144651558), RYR1 (rs143445685), @GENE$ (@VARIANT$), and DES (@VARIANT$) genes.",6180278,COL6A3;37917,CAPN3;52,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"KAT2B F307S is a loss-of-function mutation in Drosophila Drosophila Gcn5 is homologous with KAT2B and its paralog @GENE$. Gcn5E333st hemizygous animals died at late larval stage/early pupal stage as previously reported for this null mutation. The expression of Drosophila Gcn5 (hereafter referred to as Gcn5 WT) with tub-@GENE$ or another ubiquitous driver (daughterless (da)-GAL4) led to a full rescue (S3B Fig and Fig 3C). By contrast, the expression of human KAT2A and KAT2B, either alone or in combination, did not restore the viability of the mutant (Fig 3C), suggesting that the human orthologs have evolved in structure and function in comparison to Gcn5. As the mutated amino acid in KAT2B, F307, is conserved in Drosophila Gcn5 (corresponding to Gcn5 F304), we re-expressed Gcn5 F304S in the Gcn5E333st hemizygous background (Gcn5 @VARIANT$). As a negative control, we re-expressed a predicted potentially damaging KAT2B variant (S502F corresponding to Gcn5 @VARIANT$) found in a homozygous state in a healthy individual from our in-house database.",5973622,KAT2A;41343,GAL4;21239,F304S;tmVar:p|SUB|F|304|S;HGVS:p.F304S;VariantGroup:6;CorrespondingGene:39431,S478F;tmVar:p|SUB|S|478|F;HGVS:p.S478F;VariantGroup:13;CorrespondingGene:2648,0
"Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,1
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 @VARIANT$, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"@GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2).",6161649,SCUBE2;36383,VEGFR2;55639,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"However, the proband's younger brother and father were heterozygous carriers of the @VARIANT$ mutation in the @GENE$ gene while they also carried the @VARIANT$ mutation in the ABCC6 gene; they did not display any signs of cutaneous findings or hematologic disorder.       Assay of gamma-glutamyl carboxylase activity Previous studies have clearly demonstrated that the p.R1141X mutation in the @GENE$ gene in heterozygous carriers does not cause PXE.",2900916,GGCX;639,ABCC6;55559,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in @GENE$ and @VARIANT$ in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous @VARIANT$ transition in exon 20, which results in an alanine to a serine (Ala771Ser) in MYO7A. Another variation, 158-1G>A in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,2311G>T;tmVar:c|SUB|G|2311|T;HGVS:c.2311G>T;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the 497A>G (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the 580G>A (@VARIANT$) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of Cx31 and Cx26 in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against @GENE$ (a) and @GENE$ (b).,2737700,Cx26;2975,Cx31;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and @GENE$ and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated PTPN11 mutation (c.1403 C > T; @VARIANT$) and a novel, potentially pathogenic missense @GENE$ variant (@VARIANT$; p.P340S) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,neurofibromatosis 1;226,SOS1;4117,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,c.1018 C > T;tmVar:c|SUB|C|1018|T;HGVS:c.1018C>T;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0
   Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the @GENE$ gene and in exon 4 (c.872 C > G; @VARIANT$) of the @GENE$ gene were identified.,8306687,GCK;55440,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1
"The mutation G213S is expected to abolish the hydrophobic interaction of @VARIANT$ with adjacent residues. Sequences of orthologs and predicted 2D structure of human @GENE$ protein. (A) The alignment of orthologs of the human WNT10A protein. The R171 and G213 residues are represented by arrowheads. (B) The predicted 2D structure of human WNT10A protein. The R171 and G213 residues are in yellow. The 3D structure of @GENE$ is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. I312 is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of EDA with its receptors. Structure analysis of mutant residues in the three-dimensional EDA trimer. The EDA trimer is shown as a ribbon with relevant side chains rendered in spheres. The G257 and @VARIANT$ residues are in yellow and blue, respectively.",3842385,WNT10A;22525,EDA;1896,G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216,I312;tmVar:p|Allele|I|312;VariantGroup:7;CorrespondingGene:1896,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Among these four mutations, while the @VARIANT$ variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (@GENE$) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1.",4470809,OPTN;11085,TBK1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 156 to Cys.",3842385,EDA;1896,WNT10A;22525,Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of @GENE$ (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX2;9689,DUOX1;68136,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (@VARIANT$/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (@VARIANT$/p.Cys520Tyr) that cosegregated with both the AI phenotype and the @GENE$ mutation.,6785452,LAMA3;18279,ENAM;9698,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,c.1559G>A;tmVar:c|SUB|G|1559|A;HGVS:c.1559G>A;VariantGroup:6;CorrespondingGene:3909,1
"The @GENE$ R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (@VARIANT$ and R572W). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance.",6707335,NEK1;14376,alsin;23264,L106V;tmVar:p|SUB|L|106|V;HGVS:p.L106V;VariantGroup:7;CorrespondingGene:899;RS#:374191107,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, @VARIANT$, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,c.2450C>G;tmVar:c|SUB|C|2450|G;HGVS:c.2450C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"The @GENE$ variant is designated as @VARIANT$ and reported at allele frequencies of 0.0071 in ExAC, 0.0016 in TGP, and 0.0068 in GO-ESP (accessed January 23, 2018). We examined the genotype data in the TGP to determine whether these variants coincide in controls. None of 2,504 self-declared healthy individuals in TGP has both TIA1, c.1070A > G (p.Asn357Ser) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis.         We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: 179260153C/T, refSNP ID rs4935; Chr5: 179260213G/A, rs4797; Chr5: 179264731T/C, @VARIANT$; Ch5: 179264915G/T, rs1065154 ].",5868303,TIA1;20692,SQSTM1;31202,rs116621885;tmVar:rs116621885;VariantGroup:5;CorrespondingGene:7072;RS#:116621885,rs10277;tmVar:rs10277;VariantGroup:4;CorrespondingGene:8878;RS#:10277,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in @GENE$ were identified.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"(C) The EDA mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant @GENE$ allele from his mother; WNT10A mutations in the parents could not be analyzed. (D) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis. (E) The EDA mutation c.466C>T and @GENE$ mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"For example, two variants in proband P15, @VARIANT$ in @GENE$ and p. Tyr503His in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother.",8152424,PROKR2;16368,DDB1 and CUL4 associated factor 17;80067;1642,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for connexin 26 (@GENE$) and connexin 31 (@GENE$) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Further molecular studies are needed to prove the deleterious character of the @GENE$ Lys205del variant. Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, @GENE$, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,PROKR2;16368,ANOS1;55445,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, @GENE$ = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 6;4936,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and @GENE$/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"A novel missense mutation was found in @GENE$ (@VARIANT$, p.R133H). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, p.H678R and @VARIANT$, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001).",6098846,DUOXA2;57037,DUOX2;9689,c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341,p.S1067L;tmVar:p|SUB|S|1067|L;HGVS:p.S1067L;VariantGroup:4;CorrespondingGene:50506;RS#:269868;CA#:7537960,0
"Sequence alterations were detected in the @GENE$ (@VARIANT$), @GENE$ (@VARIANT$), CAPN3 (rs138172448), and DES (rs144901249) genes.",6180278,COL6A3;37917,RYR1;68069,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (rs144651558), RYR1 (@VARIANT$), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,COL6A3;37917,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of @GENE$ and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB2;2975,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,VAPB;36163,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS2;12122,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and @GENE$ mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic @GENE$ @VARIANT$ and SLC26A4 p.T410M mutations.",7067772,SLC26A4;20132,EPHA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Proband 17 inherited CHD7 @VARIANT$ and CDON @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (@GENE$ p. Arg1299Cys).",8152424,DCC;21081,CCDC88C;18903,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
"The proband's son (III.1) has inherited the @GENE$ T168fsX191 mutation, but not the TNFRSF13B/@GENE$ @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 @VARIANT$ mutation was absent in the proband's parents, indicating a de novo origin.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,1
"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A3;2223,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the S100A3 protein (c.229C>T; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in @GENE$. Mutation name is based on the full-length @GENE$ (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A13;7523,S100A3;2223,arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
" In patient AVM206, the de novo heterozygous missense variant c.2075A>G (@VARIANT$) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).      In patient AVM467, the de novo heterozygous missense variant c.676G>A (@VARIANT$) was identified in @GENE$ (table 1).",6161649,CDH2;20424,IL17RD;9717,p.Asn692Ser;tmVar:p|SUB|N|692|S;HGVS:p.N692S;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588,0
"Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"In patient AVM558, the de novo heterozygous missense variant @VARIANT$ (p.Arg565Gln) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions.",6161649,MAP4K4;7442,CDH2;20424,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,0
"Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in @GENE$, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1.",4470809,TANK-binding kinase 1;22742,OPTN;11085,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"    Sequence analyses of @GENE$ and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23A@VARIANT$/M400I @GENE$R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001.",4853519,MAN1B1;5230,GAPDH;107053,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Immunocomplex of myc-pendrin L117F, @VARIANT$ and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated @GENE$ triggered by @GENE$ stimulation.",7067772,pendrin;20132,ephrin-B2;3019,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"From these results, we were able to conclude that all the mutations, except p.R730Q, are loss-of-function mutations that affect the secretion or signaling activity of @GENE$, which strongly argues in favor of their pathogenic effect in the KS patients. In addition, the p.R730Q mutation may still have a pathogenic effect not detected in our experimental system, especially since this mutation is expected to impair proteolytic processing of Sema3A in vivo, as mentioned previously. Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,Sema3A;31358,KAL1;55445,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant @VARIANT$ and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD1;20750,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,0
"M1, @GENE$: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, CYP1B1: p.(E173*). M4, PITX2: @VARIANT$. M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"Given their offspring was mutation carriers, we might infer that II-4 and III-1 also harbored the @GENE$-@VARIANT$ mutation. Notably, not all CACNA1C-Q1916R carriers (II-3, II-6, III-4, III-5, III-7, IV-1, IV-3, IV-4 and obligate carriers II-4 and III-1) manifested the positive phenotypes (ER pattern in ECG or nocturnal SCD). This phenotypic incomplete penetrance might be modified by @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,CDON;22996,FGFR1;69065,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; @VARIANT$) c.1226A>G; p.N409S and @GENE$ (MIM 600509; NM_000352.4; rs151344623) @VARIANT$ mutations.,5505202,GBA;68040,ABCC8;68048,rs7673715;tmVar:rs7673715;VariantGroup:2;RS#:7673715,c.3989-9G>A;tmVar:c|SUB|G|3989-9|A;HGVS:c.3989-9G>A;VariantGroup:4;CorrespondingGene:6833;RS#:151344623;CA#:233276,1
"Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (@VARIANT$ and R572W). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,L106V;tmVar:p|SUB|L|106|V;HGVS:p.L106V;VariantGroup:7;CorrespondingGene:899;RS#:374191107,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (@VARIANT$; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
Protein structure analysis We performed protein structure analysis on the two @GENE$ mutations (p.R171C and @VARIANT$) and two novel @GENE$ mutations (p.G257R and @VARIANT$) that were identified in this study.,3842385,WNT10A;22525,EDA;1896,p.G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.I312M;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,PDGFRB;1960,SLC20A2;68531,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, p. R434*). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .   In vitro evaluation of a similarly truncated DUOX1 isoenzyme comprising amino acids 1 to 593 alone abolished H2O2-generating activity. Moreover, similar truncations in the highly homologous @GENE$ [p.Q686*, @VARIANT$, p.(G418fsX482);(IVS19-2A>C), p.S965fsX994] are associated with CH or severely impaired H2O2-generating activity in vitro.",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p.R701*;tmVar:p|SUB|R|701|*;HGVS:p.R701*;VariantGroup:9;CorrespondingGene:50506,0
"These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and @GENE$.       3.5. Predicted Structural Alterations and Pathogenicity of LRP6 Missense Mutations Computational prediction of the structural impact for the five LRP6 missense mutations on protein stability demonstrated that p.Met168Arg, p.Ala754Pro, and p.Asn1075Ser were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively. Particularly, @VARIANT$ and @VARIANT$ were highly destabilizing, as their DeltaDeltaGs were higher than 1.00 kcal mol-1.",8621929,LRP6;1747,WNT10A;22525,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), @GENE$ (@VARIANT$), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,RYR1;68069,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric Cx26/Cx31 connexons. Furthermore, by cotransfection of mCherry-tagged @GENE$ and GFP-tagged Cx31 in human embryonic kidney-293 cells, we demonstrated that the two connexins were able to co-assemble in vitro in the same junction plaque.",2737700,GJB6;4936,Cx26;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,1
"NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and c.850C>T (@VARIANT$) in @GENE$ and @GENE$ genes, respectively.",6292381,ANO5;100071,SGCA;9,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,R284C;tmVar:p|SUB|R|284|C;HGVS:p.R284C;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,1
"Furthermore, this CACNA1C-@VARIANT$ mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (@VARIANT$, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This SCN5A-R1193Q variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).    Gene variants of @GENE$ and @GENE$ identified in the family.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, @VARIANT$, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the SLC20A2 mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The CCDC88C missense variant @VARIANT$ was heterozygous in case P05. CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the @GENE$-mutated case P05 in our study carried additional variants in @GENE$ (DCC)@VARIANT$, and FGFR1 c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,CCDC88C;18903,DCC netrin 1 receptor;21081,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,UNC13B;31376,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Furthermore, another @GENE$ missense variant @VARIANT$ was identified in case P15. All of the remaining deleterious variants in the other seven known IHH genes were novel and unreported. Notably, the novel LoF variant @GENE$ @VARIANT$ in case P05 is de novo and evaluated as pathogenic.",8152424,PROKR2;16368,FGFR1;69065,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and @GENE$ c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,CELSR1;7665,SCRIB;44228,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in @GENE$ were identified (online supplementary table S2).",6161649,RASA1;2168,TIMP3;36322,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,1
"Similarly, our results indicate that increased transactivation associated with the @VARIANT$ PITX2 mutation is not related with altered protein stability, protein conformation or subcellular localization. Proline possesses a hydrophobic side chain, whereas threonine side chain has both hydrophilic and hydrophobic functions. Therefore, this amino acid replacement may affect protein interactions taking place in the transcriptional inhibitory domain where it is located, leading to increased PITX2 activity. In this line, an increased side chain polarity associated with amino acid substitution @VARIANT$ could also interfere protein interactions involving the first PITX2 transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, @GENE$ variants p.S36S (synonymous) and c.*38T>G (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and FOXC2-AS1 genes. FOXC2-@GENE$ encodes a lncRNA transcribed from the negative strand of FOXC2.",6338360,FOXC2;21091,AS1;736,p.P179T;tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"In our study, we identified four genetic variants in three genes (KCNQ1-p.R583H, @GENE$-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S). These variants are independently assorted in five members of an Italian LQTS family in which symptoms occurred only in the offspring of healthy parents; therefore, no variant clearly segregated with the disease. The KCNQ1-@VARIANT$ variant was previously reported to be associated with LQTS; KCNH2-p.C108Y is a novel variant; and KCNH2-p.K897T and KCNE1-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and @GENE$ channels.",5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"    Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. (C) The EDA mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant EDA allele from his mother; WNT10A mutations in the parents could not be analyzed. (D) The @GENE$ mutation c.457C>T and WNT10A mutation c.637G>A were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis. (E) The EDA mutation @VARIANT$ and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation.       Variants in the KIF5A gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2). Nonetheless, recent studies proved that @GENE$ variants have a role in ALS. According to earlier studies, KIF5A variants described in SPG10 or CMT2 patients occur in the kinesin motor domain (amino acid positions 9-327) and in the alpha-helical coiled-coil domain (amino acid positions 331-906). In contrast, variants causing ALS are found in the C-terminal cargo-binding domain (amino acids 907-1032). In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings.",6707335,SIGMAR1;39965,KIF5A;55861,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, @VARIANT$ and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in USH2A.",3125325,MYO7A;219,USH1C;77476,c.3719G>A;tmVar:c|SUB|G|3719|A;HGVS:c.3719G>A;VariantGroup:87;CorrespondingGene:4647;RS#:542400234;CA#:5545997,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"As mentioned above, some family members carrying heterozygous SCN5A @VARIANT$ mutation showed no evidence of cardiac events or cardiac diseases. The reason may be as follows: First, I:1 and II:2 who carried with the heterozygous @GENE$ p.R1865H presented no clinical syndromes because of incomplete penetrance or delayed onset. Moreover, gain-of-function mutation of SCN5A commonly induced LQTS, while loss-of-function mutation of SCN5A ordinary led to sinoatrial node dysfunction, atrioventricular block, atrial fibrillation and cardiomyopathy (e.g., ARVC/D; Blana et al.,; Han et al.,). Therefore, in this study, SCN5A p.R1865H may be the main cause of sinoatrial node dysfunction, whereas KCNH2 @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,DNAH17;72102,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"Exome analysis of the proband's DNA identified a heterozygous C to T transition at Exon 18 of @GENE$ (NG_016168.2:@VARIANT$; NM_002336.3:c.3754C>T) (Figure 1A). This sequence variant changes a glutamine codon (CAG) to a translation termination codon (TAG) at position 1252 (NP_002327.2:p.Gln1252*) and will likely subject the altered transcript to nonsense mediated decay. The mutation is not documented in the Genome Aggregation Database (gnomAD) or the Taiwan BioBank database. In addition, a missense sequence variant in @GENE$ (NG_012179.1:g.6853G>A; NM_025216.3:c.338G>A; NP_079492.2:@VARIANT$) was also identified (Figure S1A).",8621929,LRP6;1747,WNT10A;22525,g.139841C>T;tmVar:g|SUB|C|139841|T;HGVS:g.139841C>T;VariantGroup:4;CorrespondingGene:4040,p.Arg113His;tmVar:p|SUB|R|113|H;HGVS:p.R113H;VariantGroup:3;CorrespondingGene:80326;RS#:749324327;CA#:2113880,1
We identified a novel variant in the NOD2 gene (c.@VARIANT$ p.K953E) and two already described missense variants in the @GENE$ gene (S159G and @VARIANT$). The new @GENE$ missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation.,3975370,IL10RA;1196,NOD2;11156,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the SLC20A2 mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,KAL1;55445,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the @GENE$ gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"M1, @GENE$: p.(A179fs*18). M2, CYP1B1: @VARIANT$. M3, CYP1B1: p.(E173*). M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E387K);tmVar:p|SUB|E|387|K;HGVS:p.E387K;VariantGroup:2;CorrespondingGene:1545;RS#:55989760;CA#:254241,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (@VARIANT$) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"For example, patients 14 and 19 each carried one known truncating mutation (IVS28+1G>T) and a known inactivating mutation (@VARIANT$ or p.R885Q). One showed severe CH and low intelligence level, and the other showed mild CH and normal intelligence. Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (p.R110Q or @VARIANT$); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, @GENE$, @GENE$, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TG;2430,DUOX2;9689,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,0
"Among these four mutations, while the @VARIANT$ variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with @GENE$. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ @GENE$ and @VARIANT$ OFD1 (figure 3D).",7279190,OFD1;2677,FLNB;37480,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"NGS reads indicated the identification of homozygous missense pathogenic variants @VARIANT$ (p.R758C) and @VARIANT$ (R284C) in @GENE$ and @GENE$ genes, respectively.",6292381,ANO5;100071,SGCA;9,c.2272C>T;tmVar:c|SUB|C|2272|T;HGVS:c.2272C>T;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in LRP6 (g.68531T>G, @VARIANT$, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in WNT10A (g.14712G>A, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B). Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ c.4333A>G, rs761703397), and 0.0284 (@GENE$ @VARIANT$, rs147680216) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants @VARIANT$ (p.Gly505Ser) in @GENE$ and c.353A > G (p.Asn118Ser) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and @GENE$ were found in two or more independent pedigrees.",6081235,MYOD1;7857,MRPL15;32210,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in @GENE$ and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,CDH23;11142,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,1
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; @VARIANT$), and @GENE$ (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (@GENE$), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (FUS).",4470809,TBK1;22742,CSF1R;3817,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"Only one patient had a hot spot of intron variant c.5405 - 7G > A. In our study, it was reported to be pathogenic; this finding was consistent with the results of two previous studies, which indicated that the CHD7 variant was not the primary cause of KS because only 3-5% of nIHH/KS patients had a @GENE$ variant.             SEMA3A is a reported pathogenic gene of IHH that is inherited through an autosomal dominant mode. @GENE$ can affect the function of the hypothalamus pituitary gonad axis by regulating the differentiation and maturation of nerve cells, either alone or in combination with other factors (such as FGFR1). These transcription factors are widely expressed in the nervous system, and their functional defects can cause a nonreproductive phenotype, such as short stature, mental retardation, obesity, and abnormal vision. One patient presented small phallus, cryptorchidism, and irregular tooth alignment and had a novel missense variant @VARIANT$ (@VARIANT$) in the SEMA3A gene, which was identified by software as harmful.",8796337,CHD7;19067,SEMA3A;31358,c.875 T > C;tmVar:c|SUB|T|875|C;HGVS:c.875T>C;VariantGroup:0;CorrespondingGene:10371;RS#:202203360;CA#:9754374,p. Ile292Thr;tmVar:p|SUB|I|292|T;HGVS:p.I292T;VariantGroup:0;CorrespondingGene:2260;RS#:202203360,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,FUS;2521,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0
"The heterozygous SCN5A@VARIANT$ was carried by her father and sister but not carried by I:2. II:1 carried with KCNH2 @VARIANT$ as a de novo mutation, but not existed in other family members. RNA secondary structure of KCNH2 p.307_308del showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Nav1.5 protein property, SCN5A p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index.   Conclusions The digenic heterozygous @GENE$ and @GENE$ mutations were associated with young early-onset long QT syndrome and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation.       Variants in the @GENE$ gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2).",6707335,SQSTM1;31202,KIF5A;55861,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"We report digenic variants in SCRIB and @GENE$ associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,CELSR1;7665,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"  Recently, Gifford et al., identified three missense variants in @GENE$ (Gln670His), MYH7 (@VARIANT$), and @GENE$ (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MKL2;40917,NKX2-5;1482;4824,Leu387Phe;tmVar:p|SUB|L|387|F;HGVS:p.L387F;VariantGroup:4;CorrespondingGene:4625,Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, DVL3 p.R148Q, @GENE$ @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,PTK7;43672,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"As mentioned above, some family members carrying heterozygous @GENE$ p.R1865H mutation showed no evidence of cardiac events or cardiac diseases. The reason may be as follows: First, I:1 and II:2 who carried with the heterozygous SCN5A @VARIANT$ presented no clinical syndromes because of incomplete penetrance or delayed onset. Moreover, gain-of-function mutation of SCN5A commonly induced LQTS, while loss-of-function mutation of SCN5A ordinary led to sinoatrial node dysfunction, atrioventricular block, atrial fibrillation and cardiomyopathy (e.g., ARVC/D; Blana et al.,; Han et al.,). Therefore, in this study, SCN5A p.R1865H may be the main cause of sinoatrial node dysfunction, whereas KCNH2 p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether @GENE$ mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,ubiquilin-2;81830,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), @GENE$: @VARIANT$ (p.G355R) and @GENE$: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"In Family F, the GJB2/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the A194T/@GENE$, while the mother is heterozygous for the @GENE$/299-300delAT (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"   Conservation analyses at the mutant sites of @GENE$ and KCNH2 protein. SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and KCNH2 mutations. KCNH2 p.307_308del and SCN5A @VARIANT$ of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A p.R1865H. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type @GENE$ (Figure 4a), the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus lead to a reduction of structural stability.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"We observed that recombinant TEK and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (@VARIANT$), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of TEK to respond to ligand stimulation, indicating perturbed @GENE$ signaling.",5953556,CYP1B1;68035,TEK;397,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"There is a splicing site mutation c.1339 + 3A>T in @GENE$, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, @GENE$ @VARIANT$, and DCTN1 p.T1249I.",4293318,SOD1;392,ANG;74385,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,SCRIB;44228,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"This genetic synergism is also supported by the potential digenic inheritance of @GENE$ and @GENE$ mutations in Family 4. The proband, who had LRP6 p.(Asn1075Ser), p.(@VARIANT$), and WNT10A p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Her mother with @VARIANT$ in COL4A5 and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We found two novel and one previously described @GENE$ variants located in the N-terminal zinc finger domain of the protein. Cys238Arg variant lost transcriptional activity on the @GENE$ promoter reporter, while @VARIANT$ and @VARIANT$ behaved similar to wild type.",5893726,GATA4;1551,CYP17;73875,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0
"Hence, priority should be given to identifying the TCF3 @VARIANT$ mutation for preimplantation genetic diagnosis and/or chorionic villus sampling. Based on both clinical and laboratory quantification, it appears neither the TNFRSF13B/@GENE$ @VARIANT$ mutation nor the @GENE$ T168fsX191 mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The @GENE$ @VARIANT$ variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with @GENE$ variants (@VARIANT$ and R572W).",6707335,NEK1;14376,CCNF;1335,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,L106V;tmVar:p|SUB|L|106|V;HGVS:p.L106V;VariantGroup:7;CorrespondingGene:899;RS#:374191107,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The @GENE$ gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,DUSP6;55621,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"RESULTS Mutations at the gap junction proteins Cx26 and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,Cx26;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"@VARIANT$ is extremely conserved throughout evolution. The p.(Met168Arg) mutation was predicted to be highly destabilizing. (B) Alignment of P3B3 domain (a.a. 750-787 of human LRP6). The @VARIANT$ is extremely conserved among orthologs of LRP6 and @GENE$. The p.(Ala754Pro) mutation was predicted to be highly destabilizing. (C) Alignment of P4B3 domain (a.a. 1059-1097 of human LRP6). While Asparagine1075 is highly conserved among orthologs of LRP6 and LRP5, zebrafish LRP5 and Drosophila Arrow use threonine and aspartate, respectively, at this position. The p.(Asn1075Ser) mutation was predicted to destabilize local conformation. (D) Percentage of missing teeth in each tooth type of 21 patients with loss-of-function @GENE$ mutations.",8621929,LRP5;1746,LRP6;1747,Methionine168;tmVar:p|Allele|M|168;VariantGroup:9;CorrespondingGene:4040,Alanine754;tmVar:p|Allele|A|754;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) @GENE$ R524Ter; 2) PCCB G407RfrTer14; 3) @GENE$ IVS8DC; 4) OAT @VARIANT$. Two additional variants, @VARIANT$ in RYR1 and p. R498L in CACNA1S, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,GBE1;129,NUBPL;11854,"Y299Ter;tmVar:p|SUB|Y|299,ER|T;HGVS:p.Y299,ERT;VariantGroup:10;CorrespondingGene:4942",p. T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,0
"The following genes showed variants in two patients: CYP1A1 in patients 1 and 6; EVC in patients 1 (2 variants) and 7; IRX5 in patients 5 and 6; MAML1 in patients 4 and 6; MAML2 in patients 5 and 8; NOTCH2 in patients 5 and 7; RECQL4 in patients 2 and 3 and @GENE$ in patients 6 and 7 ( Table 2 ). In addition, 2 genes presented variants in 3 patients: @GENE$ (patients 6, 7 and 8) and NOTCH1 (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,WDR11;41229,MAML3;41284,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,TOR2A;25260,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ @VARIANT$, and pendrin @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different @GENE$ mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,TIA1;20692,SQSTM1;31202,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,ubiquilin-2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$).",6610752,KCNH2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,1
"Digenic Inheritance of @GENE$ and @GENE$ Mutations in Patient with Infantile Dilated Cardiomyopathy Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (@VARIANT$, p.Asp1309Asn) and a known DCM mutation in MYH7 (c.2770G > A; @VARIANT$).",6359299,LAMA4;37604,MYH7;68044,c.3925G > A;tmVar:c|SUB|G|3925|A;HGVS:c.3925G>A;VariantGroup:1;CorrespondingGene:3910;RS#:782046057;CA#:3965094,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,1
"@GENE$ forms a complex with VEGF and @GENE$ and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The @VARIANT$ (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies.",6161649,SCUBE2;36383,VEGFR2;55639,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,PROKR2;16368,DCC;21081,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Sequence alterations were detected in the COL6A3 (@VARIANT$), @GENE$ (@VARIANT$), CAPN3 (rs138172448), and @GENE$ (rs144901249) genes.",6180278,RYR1;68069,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0
"Rare @GENE$ genotypes contributed to the development of ICP in 4.3% of cases  CTRC has conventionally been regarded as being the least important gene in terms of a genetic predisposition to chronic pancreatitis, as compared with PRSS1 and @GENE$. This view received further support from two recent developments. First, some of the CTRC variants characterized by a complete or virtually complete functional loss of the affected alleles, exemplified by p.K247_@VARIANT$ and p. G217S, have been reported in unrelated healthy controls. Second, whereas a heterozygous CTRC whole gene deletion was found in trans with other genetic predisposing alleles in two subjects with familial chronic pancreatitis, a different homozygous CTRC whole gene deletion was identified in a patient with asymptomatic ICP. Employing the functionally null CTRC allele, p.K247_R254del, which increases the risk of ICP 6.4-fold, as a reference (N.B. the heterozygous SPINK1 @VARIANT$ allele confers a >10-fold increased risk), any loss-of-function variants in the CTRC gene may at most be interpreted as disease-predisposing.",3738529,CTRC;21422,SPINK1;68300,R254del;tmVar:p|DEL|254|R;HGVS:p.254delR;VariantGroup:21;CorrespondingGene:11330,p. N34S;tmVar:p|SUB|N|34|S;HGVS:p.N34S;VariantGroup:7;CorrespondingGene:6690;RS#:17107315;CA#:123440,0
"The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/@GENE$ mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"        Molecular Data All three probands carry two heterozygous variants: @GENE$, @VARIANT$ (p.Pro392Leu), and TIA1, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and SQSTM1 variants have been reported in multiple databases.",5868303,SQSTM1;31202,TIA1;20692,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation @VARIANT$ in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0
"Furthermore, this CACNA1C-@VARIANT$ mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (p.R1193Q, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This SCN5A-@VARIANT$ variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).    Gene variants of @GENE$ and @GENE$ identified in the family.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Our USH1 patient (Case #4) had segregated MYO7A:@VARIANT$ and @GENE$:@VARIANT$. Molecular analyses in mouse models have shown many interactions among the USH1 proteins. In particular, @GENE$ directly binds to PCDH15 and both proteins are expressed in an overlapping pattern in hair bundles in a mouse model.",3949687,PCDH15;23401,MYO7A;219,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,KCNE2;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and @VARIANT$ localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, @VARIANT$ located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,PTK7;43672,SCRIB;44228,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Thus, the @VARIANT$ @GENE$ mutation does not modulate levels of SEC23A. However, the @VARIANT$ @GENE$ mutation results in decreased levels of MAN1B1 in homozygous patients as well as in unaffected carriers.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"On the other hand, mutant GFP-@GENE$ @VARIANT$ and R368H showed perturbed interaction with HA-@GENE$. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327,0
"The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant. Currently, the genetic basis for the clinical heterogeneity of PFBC is not largely understood, and it cannot be explained only by a single variant. PFBC patients with biallelic variants in SLC20A2 have been reported. In 2012, Wang et al. reported that PFBC patients with compound heterozygous SLC20A2 mutations (c.362C>G, p.Ser121Cys and c.1802C>G, @VARIANT$) presented extremely severe brain calcification, accompanied by repetitive seizures, mental retardation, and developmental delay since infancy (Wang et al., 2012, 2015).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.Ser601Trp;tmVar:p|SUB|S|601|W;HGVS:p.S601W;VariantGroup:0;CorrespondingGene:6575;RS#:387906652;CA#:346848,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.",3842385,WNT10A;22525,EDA;1896,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Limb Girdle Muscular Dystrophy due to Digenic Inheritance of @GENE$ and @GENE$ Mutations We report the clinical and genetic analysis of a 63-year-old man with progressive weakness developing over more than 20 years. Prior to his initial visit, he underwent multiple neurological and rheumatological evaluations and was treated for possible inflammatory myopathy. He did not respond to any treatment that was prescribed and was referred to our center for another opinion. He underwent a neurological evaluation, electromyography, magnetic resonance imaging of his legs, and a muscle biopsy. All testing indicated a chronic myopathy without inflammatory features suggesting a genetic myopathy. Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (@VARIANT$), RYR1 (@VARIANT$), CAPN3 (rs138172448), and DES (rs144901249) genes.",6180278,DES;56469,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). While TIMP3 blocks VEGF/VEGFR2 signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,TIMP3;36322,RASA1;2168,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Digenic inheritance of MSH6 and @GENE$ variants in familial colorectal cancer Abstract We describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding @GENE$ @VARIANT$ and MUTYH @VARIANT$ in, at least, three CRC patients diagnosed before 60 years of age.",7689793,MUTYH;8156,MSH6;149,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0
"However, none of these signs were evident from metabolic work of the patient with @GENE$ @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 @VARIANT$ and @GENE$ I126V variants remain unknown.",6072915,PHKA1;1981,NDUFS8;1867,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,0
"@GENE$Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in @GENE$ were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,CCDC88;49992,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 2;2975,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"M3, @GENE$: @VARIANT$. M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in @GENE$, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. We found that mutations in the two genes segregated in the family and that the unaffected parents were healthy and carried heterozygous mutations in both @GENE$ and MAN1B1, consistent with an autosomal-recessive mode of inheritance.",4853519,MAN1B1;5230,SEC23A;4642,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (@VARIANT$) and SLC26A4: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,0
"The most frequent DCM-associated gene is TTN, mutated in 18% and 25% of sporadic and familial DCM cases, respectively compared to mutations in @GENE$ and MYBPC3 accounting for 83% of HCM cases. Some DCM-related mutations DCM or HCM disease at different ages of onset, even within the same family. The MYH7 @VARIANT$ variant was first reported by Watkins et al. in 1992 in two members of the same family affected by HCM out of 25 unrelated families screened. Interestingly, they found no disease-related or sudden death in this family, whereas disease-related deaths and sudden deaths were much more common in families carrying the MYH7 Arg403Gln variant. The p.E924K variant may, therefore, produce a more subtle phenotype. Morner et al. reported a case in a Swedish patient digenic for MYH7 p.E924K and MYBPC3 @VARIANT$ mutations, the carriers of the MYBPC3 variant apparently having late-onset HCM. MYH7 plays an important role in sarcomere function:the contracting unit of cardiomyocytes, and forms a thick filament core with @GENE$ in cardiomyocytes.",6359299,MYH7;68044,MYBPC3;215,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,Val896Met;tmVar:p|SUB|V|896|M;HGVS:p.V896M;VariantGroup:7;CorrespondingGene:4607;RS#:35078470;CA#:12837,0
"In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, @GENE$, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants @VARIANT$ and @VARIANT$ activated the CYP17 promoter similar to wt. Transcriptional activity of GATA4 variants on the CYP17A1 promoter. Human placental JEG3 cells were transfected with a @GENE$-promoter luciferase reporter construct, and the activity of wild-type (wt) and mutant GATA4 to trans-activate the promoter was tested using the Promega Dual Luciferase readout system.",5893726,SRY;48168,CYP17;73875,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0
"SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/@GENE$ binding, thus stimulating VEGF signalling (figure 3). The c.1592G>A (@VARIANT$) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant c.2075A>G (@VARIANT$) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions.",6161649,VEGFR2;55639,CDH2;20424,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.Asn692Ser;tmVar:p|SUB|N|692|S;HGVS:p.N692S;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (@VARIANT$, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,g.27546T>A;tmVar:g|SUB|T|27546|A;HGVS:g.27546T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Although the majority of @GENE$ mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging.       In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (@VARIANT$) were identified in our patient cohort. The patient (#90u) carrying the novel K631del deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The NEK1 R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in @GENE$ were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and @VARIANT$).",6707335,FUS;2521,CCNF;1335,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,0
"Mutation name is based on the full-length S100A3 (NM_002960) and @GENE$ (NM_001024210) transcripts.    Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, @VARIANT$ in @GENE$ and @VARIANT$ in S100A3, and one novel variant in S100A13, were identified.",6637284,S100A13;7523,SETDB1;32157,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MYOD1;7857,TBX6;3389,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, @VARIANT$; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the @VARIANT$ mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that @GENE$ could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 p.T410M mutations. The arrow indicates the vestibular aqueduct in the patient and the healthy control. Among sensorineural hearing loss patients EVA or the Pendred syndrome patients, a considerable number of patients carry one copy of the mutation on the SLC26A4 gene, therefore a compromised @GENE$ regulatory machinery may be involved in the pathogenesis of the syndrome.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"Among the 18 variants, three missense variations, the new @GENE$ mutation (@VARIANT$) and the known @GENE$ missense variants (S159G and @VARIANT$), caught our attention: we hypothesized that these three variants might together contribute to an increased risk of developing early onset IBD.",3975370,NOD2;11156,IL10RA;1196,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,1
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,ENG;92,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"The effects of CACNA1C-@VARIANT$ mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation. Conclusions Our results demonstrated that the loss-of-function @GENE$-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, @VARIANT$), and DMD @VARIANT$ (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous @GENE$ p.R1865H was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,p.E1028V;tmVar:p|SUB|E|1028|V;HGVS:p.E1028V;VariantGroup:5;CorrespondingGene:3757,0
"The proband of Family 3 was a compound heterozygote of p.(Ala754Pro) and p.(@VARIANT$) mutations and had fourteen missing teeth, while his father, who carried the p.(@VARIANT$) mutation, exhibited only two. Interestingly, the mother was homozygous for the p.(Ser127Thr) mutation and had all permanent teeth excepting third molars, suggesting that the variant might serve as a putative genetic modifier while not being disease-causing itself. These observations of digenic inheritance and genetic modification are supported by the significant role of @GENE$ signaling in tooth development and a direct molecular interaction between @GENE$ and LRP6.",8621929,WNT;22529,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROK2;9268,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"The @VARIANT$ (@VARIANT$) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (p.Arg565Gln) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3).",6161649,SCUBE2;36383,MAP4K4;7442,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of @GENE$ @VARIANT$ protein. In addition, the genetic marker for MAP-tumors (@GENE$ @VARIANT$) was absent in this tumor, which points toward retained MUTYH repair activity.",7689793,MSH6;149,KRAS;37990,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.34G > T;tmVar:c|SUB|G|34|T;HGVS:c.34G>T;VariantGroup:12;CorrespondingGene:3845;RS#:587782084;CA#:13137,0
"Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"Therefore, in this study, SCN5A @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas KCNH2 @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and @GENE$ p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. @GENE$ p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (c.6657T>C), USH1G (@VARIANT$; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (c.965delA), SNAI2 (@VARIANT$) and @GENE$ (@VARIANT$) genes.",7877624,MITF;4892,C2orf74;49849,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; @VARIANT$, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,g.146466A>G;tmVar:g|SUB|A|146466|G;HGVS:g.146466A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Another candidate variant in @GENE$ (@VARIANT$) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of MYH13 is mainly restricted to the extrinsic eye muscles. A nonsense variant in NOS2 (NM_000625.4: c.2059C>T, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and @GENE$ -/- mice have not been reported to manifest positive or negative motor signs.",6081235,MYH13;55780,Nos2;55473,rs7807826;tmVar:rs7807826;VariantGroup:17;RS#:7807826,p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126,0
"Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation. Allele frequency for @VARIANT$ within the population was calculated from exome sequencing of 2000 individuals and was found to be 0.1% (unpublished data from the Saudi Human Genome Project; www.saudigenomeprogram.org).",6637284,S100A3;2223,S100A13;7523,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The novel @GENE$ @VARIANT$ mutation substitutes the hydrophobic methionine168 for an arginine (p.Met168Arg) and is predicted to be ""probably damaging"", with a PolyPhen-2 score of 1. The other two LRP6 variants, c.2450C>G (p.Ser817Cys) and c.4333A>G (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the @GENE$ mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance.",8621929,LRP6;1747,WNT10A;22525,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"(A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and WNT10A mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother. (C) The EDA mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant @GENE$ allele from his mother; @GENE$ mutations in the parents could not be analyzed.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and p.R197C TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since @GENE$ localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between p.R2003H @GENE$ and @VARIANT$ OFD1 (figure 3D).",7279190,OFD1;2677,FLNB;37480,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"(A) MRI of a 31-year-old woman with compound heterozygous mutations in PKHD1, who received a diagnosis of polycystic kidneys at 17. (B) MRI of a 45-year-old woman, who carried two heterozygous variants in PKHD1, p.(@VARIANT$), and @GENE$, p.(@VARIANT$). Three additional patients showed heterozygous variants in @GENE$ (MLPA excluded large intragenic deletions/duplications).",7224062,PMM2;257,PKHD1;16336,His3124Thr;tmVar:p|SUB|H|3124|T;HGVS:p.H3124T;VariantGroup:17;CorrespondingGene:5314,Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, @GENE$ @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,KCNH2;201,LQT6;71688,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,ANG;74385,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,0
"The presence of concomitant mutations, such as the @GENE$ T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the @GENE$/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The pathogenicity of the @VARIANT$ mutation in @GENE$  is, however, questionable since we found it in five alleles from the control population. The c.5601delAAC mutation in PCDH15, leading to an in frame-deletion of a threonine residue (@VARIANT$) within the intracellular domain of the @GENE$ CD1 isoform, also warrants a special mention.",3125325,CDH23;11142,protocadherin-15;23401,p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387,p.T1868del;tmVar:p|DEL|1868|T;HGVS:p.1868delT;VariantGroup:223;CorrespondingGene:65217,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ @VARIANT$ and 2 @GENE$ missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD6;2617,FAT4;14377,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the @VARIANT$ mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain.",4470809,TANK-binding kinase 1;22742,OPTN;11085,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
Further segregation analyses of the two variants (@VARIANT$ and @VARIANT$) among the six family members of SH60 as well as clinical evaluations including audiograms excluded both p.R143W of @GENE$ and p.D771N of @GENE$ as a molecular etiology of SH60-136.,4998745,GJB2;2975,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"He also had a KAL1 deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the @GENE$ protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, @GENE$, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,anosmin-1;55445,TAC3;7560,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"      In the @GENE$ gene, a known missense variant (@VARIANT$) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel K631del deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The @GENE$ @VARIANT$ variant was also present in this patient.",6707335,TBK1;22742,NEK1;14376,I397T;tmVar:p|SUB|I|397|T;HGVS:p.I397T;VariantGroup:11;CorrespondingGene:29110;RS#:755069538;CA#:6669001,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,0
"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Additionally, a novel variant (@VARIANT$) in the 5' untranslated region of the @GENE$ gene was also detected. As the screening of untranslated regions was not in the scope of our research, we did not examine it further.   No SOD1 and @GENE$ gene variants were found in this cohort. We would like to point out that 37 of the analyzed samples were overlapping samples from a previous study and were known to be negative for SOD1 and TARDBP mutations. Still, based on earlier results, one would expect to detect SOD1 variants in the further 70 samples. Variants Detected in Minor ALS Genes By focusing on the analysis of minor ALS genes, 33 variants (31 missense and 2 splicing) were detected in 26 genes corresponding to 29 patients (27.1% of all patients,  Supplementary Table 2 ). No patients were identified as being homozygous for any of the detected variants. A patient was carrying two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene; both variants localized in the motor domain of the protein.",6707335,FUS;2521,TARDBP;7221,c.-25C > T;tmVar:c|SUB|C|-25|T;HGVS:c.-25C>T;VariantGroup:38;CorrespondingGene:2521,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with VAPB @VARIANT$ and TAF15 p.R408C with @GENE$ @VARIANT$ and SETX p.T14I).,4293318,ANG;74385,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Proband 17 inherited CHD7 @VARIANT$ and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant.",8152424,CDON;22996,FGFR1;69065,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. @GENE$ gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of KCNH2 @VARIANT$ and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"A single @GENE$ mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. The authors raised the possibility of a digenic myopathy, which up to date has not been proven.     Herein, we describe the clinical and pathological phenotype of three unrelated probands harboring the combined heterozygous @GENE$ and SQSTM1 variants in the setting of MRV or myofibrillar pathology, providing evidence that co-occurrence of these variants are associated with late-onset myopathy.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"(A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no @GENE$ large deletion within the @GENE$ locus. (C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates.",4998745,GJB6;4936,DFNB1;2975,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of @GENE$. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,DFNB1;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
" Finally, a subject with the heterozygous p.R143W mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in @GENE$ (WFS1) (NM_001145853) according to TES. However, neither @VARIANT$ in @GENE$ nor p.D771N in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).",4998745,Wolfram syndrome 1;4380,GJB2;2975,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,0
"In the second family, we identified a heterozygous @VARIANT$ mutation in PROKR2, both in a male patient with normosmic idiopathic IHH (HH12) and his asymptomatic mother. Whole-exome sequencing in the three HH1 family members allowed the identification of additional variants in the prioritized genes. We then carried out digenic combination predictions using the oligogenic resource for variant analysis (ORVAL) software. For HH1, we found the highest number of disease-causing variant pairs. Notably, a CCDC141 variant (@VARIANT$) was involved in 18 pathogenic digenic combinations. The @GENE$ variant acts in an autosomal recessive inheritance mode, based on the digenic effect prediction data. For the second patient (HH12), prediction by ORVAL allowed the identification of an interesting pathogenic digenic combination between @GENE$ and SEMA7A genes, predicted as ""dual molecular diagnosis."" The SEMA7A variant p.(Glu436Lys) is novel and predicted as a VUS by Varsome.",8446458,CCDC141;52149,DUSP6;55621,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,0
Pro-COL1A1 production and secretion in fibroblasts with mutations in @GENE$ and @GENE$. Bar graph and representative western blots showing expression of pro-COL1A1 protein in cell lysate (L) versus conditioned media (M) in wild-type (Wt); SEC23AM400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double homozygous fibroblasts.,4853519,SEC23A;4642,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"@GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,DFNB1;2975,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Compound heterozygous variants in @GENE$, @GENE$ and PTPN13 were retained. In two unrelated patients, AVM106 and AVM285, identical compound heterozygous variants were identified in DSCAML1: c.5783G>A (p.Arg1928His) and c.4574G>A (p.Arg1525His), each inherited from heterozygous carrier parents (table 2). Both variants were reported in ExAC with an allele frequency <0.001, and they were predicted in silico to be highly deleterious (GERP++>4 and CADD>30 for both). In patient AVM226, we identified the compound heterozygous variants c.3775G>A (p.Val1259Ile) and c.2966A>T (p.Gln989Leu) in DSCAM (table 2). DSCAML1 and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and @VARIANT$ (p.Ser334Thr) were identified in PTPN13 (table 2).",6161649,DSCAML1;79549,DSCAM;74393,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"We finally found evidence of four potential novel candidate genes contributing to IHH: coiled-coil domain containing 88C (CCDC88C), cell adhesion associated, oncogene regulated (CDON), glutamate decarboxylase like 1 (GADL1), and sprouty related EVH1 domain containing 3 (@GENE$). The CCDC88C missense variant @VARIANT$ was heterozygous in case P05. CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the @GENE$-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)p. Gln91Arg, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,SPRED3;28061,CCDC88C;18903,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); SEC23A M400I/+ heterozygous; SEC23AM400I/+ @GENE$R334C/+ double heterozygous; and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001.",4853519,MAN1B1;5230,GAPDH;107053,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"GJB2 Single Heterozygotes where @GENE$ was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (rs121908073), and a novel variant, @VARIANT$ of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1).",4998745,DFNB1;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.W482R;tmVar:p|SUB|W|482|R;HGVS:p.W482R;VariantGroup:0;CorrespondingGene:117531;RS#:754142954;CA#:5081956,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 @VARIANT$, @GENE$ p.P642R, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"For co-transfection experiments, 2 mug (1 mug KCNQ1-WT + 1 mug KCNE1-WT or 1 mug KCNQ1-@VARIANT$ + 1 mug @GENE$-WT) or 3 mug (1.5 mug KCNH2-WT + 1.5 mug KCNH2-@VARIANT$ or 1.5 mug @GENE$-WT + 1.5 mug empty vector) plasmid per dish were used.",5578023,KCNE1;3753,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,0
"Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and @VARIANT$ variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,SOD1;392,ANG;74385,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the @GENE$ missense changes (NM_013254.3:@VARIANT$; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.2086G>A;tmVar:c|SUB|G|2086|A;HGVS:c.2086G>A;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, @VARIANT$), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, @VARIANT$) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of @GENE$ p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,LAMA2;37306,KCNH2;201,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,c.A3083T;tmVar:c|SUB|A|3083|T;HGVS:c.3083A>T;VariantGroup:5;CorrespondingGene:3757,0
"In this family, the patient (II: 1) with digenic heterozygous mutations of KCNH2 @VARIANT$ and @GENE$ @VARIANT$ presented the earliest phenotype of LQTS, and she suffered from syncope, torsades de pointes, and ventricular fibrillation more frequently at rest, whereas the members (I:1 and II:2) without KCNH2 p.307_308del showed normal QT intervals and cardiac function. The changed site of KCNH2 p.307_308 was highly conserved across most species, suggesting p.307_308 of KCNH2 protein playing a significant role in function. The result indicated that the novel genetic background, @GENE$ p.307_308del, may affect and even induce the phenotype of LQTS.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"The other two LRP6 variants, c.2450C>G (@VARIANT$) and c.4333A>G (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the WNT10A mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance. Segregation analysis of the parent-child trio revealed that the father, who was hypodontic, carried all three LRP6 variants but not the WNT10A mutation, which was found in the mother. This segregation pattern of mutations suggested a plausible synergetic effect from the @GENE$ and @GENE$ mutations, which caused thirteen missing teeth in the proband.",8621929,LRP6;1747,WNT10A;22525,p.Ser817Cys;tmVar:p|SUB|S|817|C;HGVS:p.S817C;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother. Proband 17 inherited @GENE$ p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,DDB1 and CUL4 associated factor 17;80067;1642,CHD7;19067,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Three of these individuals were heterozygous, but none was homozygous for @VARIANT$. Sequencing of the @GENE$ intronic and 5'-flanking sequences was performed in the affected patients and no other variants were identified (data not shown). The novel truncated variant in @GENE$ was not found in our ""in-house"" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The c.229C>T (p.R77C) variant in S100A3 and @VARIANT$ (p.I80Gfs*13) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.",6637284,S100A3;2223,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, @VARIANT$, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,c.379T>A;tmVar:c|SUB|T|379|A;HGVS:c.379T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Rare CTRC genotypes contributed to the development of ICP in 4.3% of cases  CTRC has conventionally been regarded as being the least important gene in terms of a genetic predisposition to chronic pancreatitis, as compared with @GENE$ and @GENE$. This view received further support from two recent developments. First, some of the CTRC variants characterized by a complete or virtually complete functional loss of the affected alleles, exemplified by p.K247_R254del and @VARIANT$, have been reported in unrelated healthy controls. Second, whereas a heterozygous CTRC whole gene deletion was found in trans with other genetic predisposing alleles in two subjects with familial chronic pancreatitis, a different homozygous CTRC whole gene deletion was identified in a patient with asymptomatic ICP. Employing the functionally null CTRC allele, p.K247_R254del, which increases the risk of ICP 6.4-fold, as a reference (N.B. the heterozygous SPINK1 @VARIANT$ allele confers a >10-fold increased risk), any loss-of-function variants in the CTRC gene may at most be interpreted as disease-predisposing.",3738529,PRSS1;134623,SPINK1;68300,p. G217S;tmVar:p|SUB|G|217|S;HGVS:p.G217S;VariantGroup:18;CorrespondingGene:11330;RS#:202058123;CA#:613437,p. N34S;tmVar:p|SUB|N|34|S;HGVS:p.N34S;VariantGroup:7;CorrespondingGene:6690;RS#:17107315;CA#:123440,0
"The novel truncated variant in @GENE$ was not found in our ""in-house"" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The @VARIANT$ (p.R77C) variant in @GENE$ and c.238-241delATTG (@VARIANT$) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.",6637284,S100A13;7523,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, @VARIANT$, in one of the c.235delC carriers (SH107-225) (Figure 4A). She inherited @VARIANT$ of GJB2 from her father and did not have any known large genomic deletions within the @GENE$ locus (Figure 4B).",4998745,MITF;4892,DFNB1;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
Causative heterozygous mutations in @GENE$ (p.N382S/@VARIANT$) and @GENE$ (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.,7026993,GFI1;3854,MYO6;56417,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant c.190G>A(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.   CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant c.464G>T(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and @GENE$ has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).",7549550,RIPPLY1;138181,MYOD1;7857,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,0
"Mutations in genes involved in WNT/beta-catenin signaling, including AXIN2 @GENE$, @GENE$, LRP6, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(@VARIANT$), @VARIANT$, and p.(Asn1075Ser).",8621929,WNT10A;22525,WNT10B;20721,Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.(Ala754Pro);tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"   The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,pendrin;20132,EphA2;20929,Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ @VARIANT$, DVL3 p.R148Q, PTK7 @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,alsin;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Sequence alterations were detected in the COL6A3 (rs144651558), @GENE$ (@VARIANT$), @GENE$ (@VARIANT$), and DES (rs144901249) genes.",6180278,RYR1;68069,CAPN3;52,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The genotypes of @GENE$ (NM_001257180.2: c.1787A>G, @VARIANT$) and PDGFRB (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown. Regarding SLC20A2, A/G = heterozygous mutation carrier, and A/A = wild type; regarding @GENE$, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Four potential pathogenic variants, including @GENE$ @VARIANT$ (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, @VARIANT$), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0
"    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of MEOX1 is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MYOD1;7857,TBX6;3389,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"The most common mutation was @VARIANT$ (DUOX2: c.3329G>A), which was found in 5 patients, accounting for 11% of all the cases. Of the 3 novel variants in DUOX2, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and p.D137E and p.E389K were missense mutations located in the peroxidase-like domain (Fig. S3A).  A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, @GENE$ and TPO).  A total of 6 @GENE$ variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B).",7248516,DUOXA2;57037,TPO;461,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:12;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The results showed that the two @GENE$ variants @VARIANT$ and p.(C498R) were associated with a 22%-28% reduced transactivation (Fig 5A). Only one of the two identified @GENE$ variants, @VARIANT$, could be cloned for functional evaluation.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in  Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for EVC, @GENE$, GLI2, RIPK4 and EYA1; and RET for PIK3R3 with PTPN11, which also is connected with RIPK4. RIPK4 itself is a central node for @GENE$, CUL4B, GLI3 and PTPN11.",6726737,FGF10;3284,ZBTB16;21214,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Moreover, given the complex association of LQTS mutants in the individuals of the family and the potential causative role of each mutation, and also based on in silico analysis and on evidence from previous studies, we focused on the in vitro functional characterization of the @GENE$-@VARIANT$ and @GENE$-@VARIANT$ variants.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,1
"Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).",8152424,DCC;21081,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in @GENE$ were identified (online supplementary table S2).",6161649,ENG;92,SCUBE2;36383,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,1
"The @VARIANT$ is not directly involved in Zn binding but is situated next to Cys220 which binds the Zn atom, and therefore, the mutation Gly221Arg will disrupt the Zn binding, leading to a non-functional GATA4. The Cys238 binds Zn and its mutation to arginine leads to loss of Zn binding (Figure 4). @GENE$ regulates the expression of multiple genes coding for hormones or components of the steroidogenic pathway during testis development and function. In Gata4ki mice with @VARIANT$ mutation interaction of Gata4 with cofactor Fog is abrogated, and consequently animals display anomalies of testis development. Moreover, GATA4 functionally interacts with NR5A1 in Sertoli cell cultures to positively regulate the expression of AMH, and therefore, it has been reported that mutations in NR5A1 may cause 46,XY DSD due to lack of interaction with @GENE$. No gonadal involvement is mostly detected in families with GATA4 mutations and isolated CHD, possibly because some of the variants retain some DNA-binding activity and exhibit different degrees of transcriptional activation on gonadal promoters and thus, remain able to synergize with NR5A1.",5893726,GATA4;1551,GATA;6699,Gly221;tmVar:p|Allele|G|221;VariantGroup:4;RS#:398122402(Expired),p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,VPS13C;41188,MYOD1;7857,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and @VARIANT$; (B) in the NOD2 exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the @VARIANT$ substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,R351G;tmVar:p|SUB|R|351|G;HGVS:p.R351G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (c.6657T>C), @GENE$ (@VARIANT$; p.L16V) and USH2A (@VARIANT$).",3125325,MYO7A;219,USH1G;56113,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,1
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,DNAH17;72102,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the CCDC88C @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,DCC;21081,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous @GENE$ nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of @GENE$ (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX2;9689,DUOX1;68136,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and C104R (c.310T>C) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the TNFRSF13B/TACI @VARIANT$ mutation.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). The @VARIANT$ (p.His596Arg) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"On the contrary, the functionality of the @GENE$-@VARIANT$ channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and @GENE$-WT/KCNH2-@VARIANT$ heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Genetic screening of the KCNH2 gene also revealed the @GENE$-@VARIANT$ (p.K897T) common variant (MAF = 0.187). This variant was previously reported to be a possible negative modifier of IKr that is able to alter channel kinetics, predispose to arrhythmic events, affect the repolarization process, and alter the length of the QT interval. Another common variant in the @GENE$ gene (@VARIANT$) results in the substitution of the glycine residue with serine at position 38 (p.G38S) and is located in the C-terminal cytoplasmic domain.",5578023,KCNH2;201,KCNE1;3753,c.A2690C;tmVar:c|SUB|A|2690|C;HGVS:c.2690A>C;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,c.G112A;tmVar:c|SUB|G|112|A;HGVS:c.112G>A;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The @GENE$ P291fsinsC (@VARIANT$) mutation is the most common of all MODY mutations: it results in a frameshift and premature termination codon. There is no doubt over its pathogenicity and both sisters had inherited this mutation from their diabetic father. The @GENE$ @VARIANT$ mutation was first described by Furuta et al. in 1997 and is the most common HNF4A mutation, reported in the literature in 15 families from multiple countries. .",4090307,HNF1A;459,HNF4A;395,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent @GENE$ variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: p.(C498R) and @VARIANT$; PITX2: @VARIANT$).,6338360,PITX2;55454,FOXC2;21091,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The four other variants (@GENE$ @VARIANT$, CELSR1 p.R1057C and @GENE$ @VARIANT$) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,CELSR1;7665,SCRIB;44228,p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,0
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the 497A>G (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the 580G>A (@VARIANT$) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of @GENE$ and @GENE$ in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against Cx26 (a) and Cx31 (b).,2737700,Cx31;7338,Cx26;2975,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"In Family F, the GJB2/235delC was inherited from the unaffected father and the A194T of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the @VARIANT$/GJB3, while the mother is heterozygous for the @GENE$/@VARIANT$ (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,0
"Circles: females; squares: males; white symbols: not included in the study; white symbols with genotype: unaffected; black symbols: pulmonary fibrosis affected; +: wild-type ""C"" allele of S100A3/wild-type sequence of S100A13; -: mutant ""T"" allele of @GENE$ (@VARIANT$)/4 bp deletion of @GENE$ (@VARIANT$).",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1
"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS6;10318,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and @VARIANT$, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,c.1051A > G;tmVar:c|SUB|A|1051|G;HGVS:c.1051A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"Of the 3 novel variants in DUOX2, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and @VARIANT$ and @VARIANT$ were missense mutations located in the peroxidase-like domain (Fig. S3A).  A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, @GENE$ and @GENE$).",7248516,DUOXA2;57037,TPO;461,p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506,p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991,0
"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (p.Gln106Arg, at 0.2%; p.Val134Gly, at 0.0008%; @VARIANT$ at 0.2%; and PROKR2 @VARIANT$ at 0.0008%). Discussion The overall prevalence of GNRHR mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies. Four patients had biallelic mutations (including two patients with a novel frameshift deletion) and one patient had a digenic (@GENE$/@GENE$) heterozygous mutation.",5527354,GNRHR;350,PROKR2;16368,p.Arg262Gln;tmVar:p|SUB|R|262|Q;HGVS:p.R262Q;VariantGroup:5;CorrespondingGene:2798;RS#:104893837;CA#:130198,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys.",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (R1499H) were detected in the @GENE$ gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The penetrance was also incomplete, which was modified by a gain-of-functional @GENE$-@VARIANT$ variant and sex. The result strengthens the evidence that males are typically at higher risk of SCD, and the inheritance of ERS may be an oligogenic pattern rather than a monogenic model. The targeted mutation screening will effectively guide disease prevention and offspring fertility in the family. Isoproterenol, in theory, may be a putative pharmacologic option to improve the function of @GENE$-@VARIANT$ mutant channel.",5426766,SCN5A;22738,CACNA1C;55484,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, @VARIANT$) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
The c.229C>T (@VARIANT$) variant in @GENE$ and c.238-241delATTG (@VARIANT$) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2.,6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,1
"Biallelic pathogenic variants in the @GENE$ gene may lead to MKS3, with overlapping symptoms to ADPKD, including renal cysts and central nervous dysplasia, among which the latter was not evidently manifested in Family 24. One possible explanation for this could be that @VARIANT$ (@VARIANT$) was possibly a hypomorphic variant. 47  The @GENE$ gene is expressed in a subset of embryonic tissues 48  and is involved in cilia formation.",8256360,TMEM67;71886,TMEM107;12052,c.637C > T;tmVar:c|SUB|C|637|T;HGVS:c.637C>T;VariantGroup:3;CorrespondingGene:5314;RS#:866575098;CA#:138924774,p.R213C;tmVar:p|SUB|R|213|C;HGVS:p.R213C;VariantGroup:3;CorrespondingGene:91147;RS#:866575098,0
"Specifically, variant @GENE$-@VARIANT$ was not found in 54 samples of the Cypriot general population nor in 305 samples with FMH tested at our setting. Also this variant was never reported in the ExAC genomes database. Variant @GENE$-@VARIANT$ was neither found in 81 healthy individuals of the Cypriot general population nor was it present in any of 159 TBMN patients' DNA.",5954460,COL4A5;133559,LAMA5;4060,p.Asp654Tyr;tmVar:p|SUB|D|654|Y;HGVS:p.D654Y;VariantGroup:4;CorrespondingGene:1287;RS#:1131692060,p.Pro1243Leu;tmVar:p|SUB|P|1243|L;HGVS:p.P1243L;VariantGroup:2;CorrespondingGene:3911;RS#:756101090;CA#:9942875,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant @GENE$ proteins was assessed in HUVECs using immunofluorescence analysis.",5953556,CYP1B1;68035,TEK;397,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"@GENE$ mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"A concomitant variant (@VARIANT$, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This SCN5A-R1193Q variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).    Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (c.5747A>G, @VARIANT$) in CACNA1C.",5426766,CACNA1C;55484,SCN5A;22738,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) GBE1 R524Ter; 2) PCCB G407RfrTer14; 3) NUBPL IVS8DC; 4) @GENE$ @VARIANT$. Two additional variants, @VARIANT$ in @GENE$ and p. R498L in CACNA1S, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,OAT;231,RYR1;68069,"Y299Ter;tmVar:p|SUB|Y|299,ER|T;HGVS:p.Y299,ERT;VariantGroup:10;CorrespondingGene:4942",p. T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,VAPB;36163,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"We propose that cysteine to arginine change in position 238 of @GENE$ lacks activity to bind DNA reducing the transactivation of @GENE$ critically.  By contrast, variants @VARIANT$ and p@VARIANT$ found in cases 2 and 3 did not affect CYP17 promoter activity.",5893726,GATA4;1551,AMH;68060,p.Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,PROKR2;16368,FGFR1;69065,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,alsin;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"We identified four genetic variants (KCNQ1-@VARIANT$, @GENE$-p.C108Y, KCNH2-p.K897T, and @GENE$-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely @VARIANT$, p.P79T, p.S82T, p. A85P, p.L86F, @VARIANT$, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.Q70Hfs*8;tmVar:p|FS|Q|70|H|8;HGVS:p.Q70HfsX8;VariantGroup:8;CorrespondingGene:6012,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,0
"Mutations in the MAT1A gene are reported to cause MAT I/III deficiency, a condition characterized by persistent hypermethioninemia not accompanied by elevated homocysteine or tyrosine.36 Disturbance in the methionine cycle has been found to cause NTDs in experimental models in the mouse.31 However, clinical manifestations of MAT deficiency are variable, including no neurological abnormalities.36 Also, a stop-gain variant @VARIANT$ (@VARIANT$) was detected in the nitric oxide synthase 2 (NOS2) gene (Figure 2C). In ExAC, 20 LoF variants are reported in NOS2 with a pLI = 0, suggesting tolerance of LoF and low confidence of causal effect. However, @GENE$ has been previously associated with a cranial NTD phenotype where A/G genotype of the rs4795067 SNP within NOS2 was shown to be associated specifically with increased cranial NTD risk.37                            DNA sequence electropherograms, protein conservations and position of the genetic variants in relation to the protein domains. Protein domain figures were created with MutationMapper (http://www.cbioportal.org/mutation_mapper.jsp, v1.0.1). (A) @GENE$ frameshift deletion mutation.",5887939,NOS2;55473,PDGFRA;31361,c.1893C>A;tmVar:c|SUB|C|1893|A;HGVS:c.1893C>A;VariantGroup:18;CorrespondingGene:23513;RS#:745973254;CA#:187609296,p.Tyr631Ter;tmVar:p|SUB|Y|631|X;HGVS:p.Y631X;VariantGroup:45;CorrespondingGene:4843,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a @VARIANT$ of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"          Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the GGCX and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a valine by methionine at position 255 (@VARIANT$) of the @GENE$ enzyme was detected (Fig. 3b).",2900916,VKORC1;11416,gamma-glutamyl carboxylase;639,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"(A) In addition to @VARIANT$ in @GENE$, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,1
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,gap junction protein beta 3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2).",7549550,RIPPLY1;138181,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"These two individuals were heterozygous carriers of p.R1141X mutation in @GENE$ and @VARIANT$ in GGCX. Since heterozygous carriers of @VARIANT$ in ABCC6 alone do not manifest PXE and @GENE$ mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance.",2900916,ABCC6;55559,GGCX;639,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,GJB3;7338,Cx26;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"During mesoderm development, the expression of MEOX1 is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.   CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in @GENE$ was also identified.",7549550,TBX6;3389,MYOD1;7857,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"The @GENE$ c.1787A>G (@VARIANT$) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the @GENE$ @VARIANT$ (p.Arg106Pro) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). The c.1787A>G (@VARIANT$) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"                                 CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 @VARIANT$ and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. @GENE$ p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of TCF3 and C104R (@VARIANT$) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ T168fsX191 mutation, but not the TNFRSF13B/TACI C104R mutation.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Sanger sequencing was further performed for validation of the identified variants and analysis of their segregation within each family, using corresponding primer sets for LRP6 and @GENE$. For numbering gDNA and cDNA mutation positions, the subject's sequence variants were compared to human reference sequences NG_016168.2 and NM_002336.3 for LRP6 and NG_012179.1 and NM_025216.3 for WNT10A.       2.3. Prediction of Structural Alterations Caused by LRP6 Mutations To investigate the potential impact of the identified @GENE$ missense mutations on protein structure we conducted computational predictions using PremPS, recently developed software that has been shown to outperform currently available methods. For prediction of @VARIANT$ and p.Met168Arg the PDB (Protein Data Bank) structure of 3S94 was used, which constituted a crystal structure of the human LRP6 extracellular domain (E1E2). On the other hand, 4A0P, the crystal structure of LRP6-E3E4, was employed for prediction of @VARIANT$, p.Ser817Cys, and p.Asn1075Ser. ""A chain"" was selected in all predictions, and mutation specified manually.",8621929,WNT10A;22525,LRP6;1747,p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and @GENE$: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, @VARIANT$, p.L86F, p.F112S, p.R127L, @VARIANT$, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p. A85P;tmVar:p|SUB|A|85|P;HGVS:p.A85P;VariantGroup:78;CorrespondingGene:6012,p.G149D;tmVar:p|SUB|G|149|D;HGVS:p.G149D;VariantGroup:15;CorrespondingGene:1805;RS#:777651623,0
"          Aberrant regulation of pathogenic forms of @GENE$ via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/@GENE$ regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin @VARIANT$ was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected.",7067772,pendrin;20132,ephrin-B2;3019,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, @VARIANT$, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,c.2450C>G;tmVar:c|SUB|C|2450|G;HGVS:c.2450C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The @GENE$ gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,DUSP6;55621,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  @GENE$, 23  @GENE$, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS.",7689793,EBNA1BP2;4969,TRIP6;37757,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,1
"MTHFR, methylenetetrahydrofolate reductase                             One individual (283F06) was heterozygous for a novel missense variant in the catalytic N-terminal domain of the methylenetetrahydrofolate reductase (@GENE$) gene (c.601C>T; p.His201Tyr) (Figure 2D), which was predicted to be damaging by all 6 mutation predictors tested (Table 1). This individual was also heterozygous for the common MTHFR c.677C>T variant, and also carries a rare glycine decarboxylase (@GENE$) @VARIANT$ missense variant, possibly indicating a compromised FOCM in this patient. Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (@VARIANT$; p.Val2517Met) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (CELSR1) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3).",5887939,MTHFR;4349,GLDC;141,c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332,c.7549G>A;tmVar:c|SUB|G|7549|A;HGVS:c.7549G>A;VariantGroup:14;CorrespondingGene:9620;RS#:1261513383,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,PTK7;43672,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,LQT2;201,LQT6;71688,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Among these four mutations, while the c.503T>G variant in @GENE$ is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, @VARIANT$), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,rs2302686;tmVar:rs2302686;VariantGroup:2;CorrespondingGene:4040;RS#:2302686,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Using SIFT and PolyPhen, the @VARIANT$ variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, c.1070A > G (@VARIANT$) and @GENE$, @VARIANT$ (p.Pro392Leu).",5868303,TIA1;20692,SQSTM1;31202,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,c.1175C > T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,1
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"@GENE$ encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD.",6707335,NEFH;40755,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the @VARIANT$ mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the @GENE$ binding domain.",4470809,TBK1;22742,OPTN;11085,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"PKD1 sequencing identified a likely pathogenic variant, p.(Asn2167Asp), absent in parents, and a second maternally inherited variant, p.(@VARIANT$). This is extremely rare (never reported before, absent in GnomAD), but with benign computational predictions, and it was classified as hypomorphic. We cannot formally test if variants in these two patients are in trans, but we presume they contributed to the severe clinical expression. In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(Cys331Thr) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly).",7224062,PKD1;250,PKD2;20104,Ala561Val;tmVar:p|SUB|A|561|V;HGVS:p.A561V;VariantGroup:10;CorrespondingGene:5311;RS#:542353495,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,SPTBN4;11879,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"          Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the GGCX and @GENE$ genes. The results demonstrated the presence of two missense mutations in @GENE$. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a @VARIANT$ (p.V255M) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b).",2900916,VKORC1;11416,GGCX;639,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,valine by methionine at position 255;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Moreover, patients carrying a @GENE$ @VARIANT$ mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (L1038P) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYBPC3;215,Pro943Leu;tmVar:p|SUB|P|943|L;HGVS:p.P943L;VariantGroup:5;CorrespondingGene:3910;RS#:387907365;CA#:143749,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0
"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS. The novel @GENE$ @VARIANT$ mutation substitutes the hydrophobic methionine168 for an arginine (p.Met168Arg) and is predicted to be ""probably damaging"", with a PolyPhen-2 score of 1.",8621929,WNT10A;22525,LRP6;1747,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT6;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In addition, in a different individual, the @GENE$ @VARIANT$ mutation was identified in association with a mutation in a second gene, @GENE$ (c.275T>C;@VARIANT$; MIM 138850; NM_000406.2), implicating digenic inheritance of this disorder as well.",5505202,WDR11;41229,GNRHR;350,p.A435T;tmVar:p|SUB|A|435|T;HGVS:p.A435T;VariantGroup:0;CorrespondingGene:55717;RS#:318240760;CA#:130157,p.L92P;tmVar:p|SUB|L|92|P;HGVS:p.L92P;VariantGroup:8;CorrespondingGene:2629;RS#:1141815,1
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, @VARIANT$, p. A85P, p.L86F, @VARIANT$, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.S82T;tmVar:p|SUB|S|82|T;HGVS:p.S82T;VariantGroup:111;CorrespondingGene:6012,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,0
"On the other hand, the WNT10A p.(@VARIANT$) mutation has been shown to cause hypodontia or no tooth agenesis in heterozygous carriers. The mother who passed this mutation had a full set of permanent dentition except for maxillary third molars. However, when combined with the LRP6 mutations, it led to a severe phenotype of thirteen missing teeth in the proband. This genetic synergism is also supported by the potential digenic inheritance of @GENE$ and @GENE$ mutations in Family 4. The proband, who had LRP6 p.(Asn1075Ser), p.(@VARIANT$), and WNT10A p.(Glu167Gln) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"(A) Segregation of the KCNQ1-@VARIANT$, @GENE$-p.C108Y, KCNH2-p.K897T, and @GENE$-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT5;71688,LQT2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and @VARIANT$; (B) in the NOD2 exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,R351G;tmVar:p|SUB|R|351|G;HGVS:p.R351G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,0
"@GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,DFNB1;2975,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"    Sanger sequencing Sanger sequencing was performed on available samples for confirmation of @GENE$ and @GENE$ variants in family members to perform segregation analysis. Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (p.N382S/@VARIANT$) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, @GENE$ = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 6;4936,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In addition, we have confirmed that immunoreactive signal corresponding to the anti-ephrin-B2 antibody was colocalized with that to the anti-@GENE$ antibody in the inner ear (Supplementary Fig. 3g). These results suggest an important role of ephrin-B2 as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1.           Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, @VARIANT$ were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated @GENE$. Immunocomplex of myc-pendrin L117F, @VARIANT$ and F355L was not affected.",7067772,EphA2;20929,pendrin;20132,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"KCNH2-@VARIANT$ was previously associated with a prolonged QT interval in several different populations and can alter the biophysical properties of mutant channels (current density, activation, inactivation, and recovery from inactivation) and exacerbate the IKr reduction caused by other KCNH2 mutations. KCNH2-p.K897T affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, @GENE$-p.G38S is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia. Nevertheless, in vitro studies demonstrated that the KCNE1-@VARIANT$ variant causes only a mild reduction of the delayed rectifier K+ currents. Therefore, G38S could be a genetic modifier, but the evidence available does not suggest it has an overt effect on the function of the @GENE$ and KCNH2 channels.",5578023,KCNE1;3753,KCNQ1;85014,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare glycine decarboxylase (GLDC) c.2203G>T missense variant, possibly indicating a compromised FOCM in this patient. Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (c.7549G>A; @VARIANT$) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (@GENE$) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3).",5887939,MTHFR;4349,CELSR1;7665,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,p.Val2517Met;tmVar:p|SUB|V|2517|M;HGVS:p.V2517M;VariantGroup:14;CorrespondingGene:9620;RS#:1261513383,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"We identified a novel variant in BBS1 patient #10 c.1285dup (p.(Arg429Profs*72)) defined as pathogenic that segregates with phenotype together with c.46A > T (@VARIANT$, defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, was identified in patient #3. BBS1, @GENE$ and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS2;12122,BBS7;12395,p.(Ser16Cys);tmVar:p|SUB|S|16|C;HGVS:p.S16C;VariantGroup:5;CorrespondingGene:582;RS#:772917364,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"While tagged versions of EphA2 G355R and EphA2 @VARIANT$ were effectively precipitated with Fc-fusion ephrin-A1 compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down @GENE$ G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 G355R and EphA2 T511M with @GENE$ induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as H723R, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum. Low temperature incubation and salicylate treatment of cultured cells, which are thought to help with protein-folding processes, rescues the membrane localization of H723R. On the other hand, mis-localization of pendrin @VARIANT$ from the plasma membrane is not restored by these treatments, suggesting these mutations may affect pendrin trafficking from the Golgi to the plasma membrane but not protein-folding.",7067772,EphA2;20929,pendrin;20132,T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Also patient 16672, a 42 year old man, found out to have renal cysts at the age of 40, together with multiple hepatic cysts; he carried a heterozygous variant of unknown significance, p.(@VARIANT$). Finally, patient 16542 was diagnosed with PKD at the age of 30 years, after the onset of arterial hypertension (MRI is shown in Figure 3B); she had normal renal function at last evaluation (45 years). Her father died at the age of 79, he had type 2 diabetes requiring insulin treatment, renal and hepatic cysts detected at ultrasonography and normal renal function. The patient carried a heterozygous variant of unknown significance in @GENE$, p.(His3124Tyr), defined as likely pathogenic in ClinVar, and a missense variant p.(@VARIANT$) in PMM2, classified as likely pathogenic. Recessive mutations in PMM2 were reported as associated to hyperinsulinemic hypoglycemia (HI) and @GENE$ (Cabezas et al.,).",7224062,PKHD1;16336,PKD;55680,Arg3913Cys;tmVar:p|SUB|R|3913|C;HGVS:p.R3913C;VariantGroup:1;CorrespondingGene:5314;RS#:144118755,Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895,0
"Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (c.7549G>A; p.Val2517Met) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (@GENE$) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3). Heterozygous missense mutations in CELSR1 gene have previously been reported in a number of NTD patients.38, 39, 40 Two novel and 3 rare SCRIB missense variants were identified in 5 anencephaly cases (Table 1 and Table S2 in Appendix S3). SCRIB mutations have previously been implicated in human craniorachischisis.40 Three samples carried more than 1 variant within the same gene: sample 01F292 had 2 rare @GENE$ variants (@VARIANT$; c.6607C>T), f11-278 had 1 novel (c.8335C>G) and 1 rare (c.5587C>T) variants in CELSR3 and 693F06 had 2 rare missense variants (c.3109G>C; @VARIANT$) in NOS2.",5887939,CELSR1;7665,FAT4;14377,c.739C>A;tmVar:c|SUB|C|739|A;HGVS:c.739C>A;VariantGroup:16;CorrespondingGene:79633;RS#:191329848;CA#:3071852,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:32;CorrespondingGene:4843;RS#:1223229852,0
"The mother did not carry this luteinizing hormone/choriogonadotropin receptor (@GENE$) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the @GENE$, SRY, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant @VARIANT$ lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants @VARIANT$ and Pro226Leu activated the CYP17 promoter similar to wt.",5893726,LHCGR;37276,AMH;68060,Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"Since @GENE$ is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"This patient with the @VARIANT$ @GENE$ missense mutation also had a hemizygous @GENE$ deletion of the completely conserved @VARIANT$ within the whey-acidic-protein (WAP) domain that forms a disulphide bridge with Cys134 of anosmin-1 (Figure S1C,D).",3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,Cys163;tmVar:p|Allele|C|163;VariantGroup:9;CorrespondingGene:3730,1
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,VPS13C;41188,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
  LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and @GENE$ @VARIANT$ by WES and predisposing genes analyses. More cellular and animal research is needed to further investigate whether the coexisting interaction of @GENE$ @VARIANT$ and SCN5A p.R1865H increases the risk of the early-onset LQTS and sinoatrial node dysfunction.,8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Although @VARIANT$ did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the @GENE$ protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, @GENE$, PROK2, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,anosmin-1;55445,FGFR1;69065,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"@GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; @VARIANT$) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, @GENE$, LRP5, LRP6, @GENE$, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,LRP4;17964,ROR1;3675,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Interestingly, we found just one patient with variants in @GENE$, the most frequently detected gene in @GENE$ patients. We identified a novel variant in BBS1 patient #10 c.1285dup (@VARIANT$) defined as pathogenic that segregates with phenotype together with c.46A > T (p.(Ser16Cys), defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (@VARIANT$; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*).",6567512,BBS1;11641,BBS;12122,"p.(Arg429Profs*72);tmVar:p|FS|R,P|429|RO|72;HGVS:p.R,P429ROfsX72;VariantGroup:28;CorrespondingGene:582",c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,0
GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%). No significant change was observed with HA-TEK G743A with GFP-@GENE$ @VARIANT$ as compared to WT proteins (Fig. 2).,5953556,TEK;397,CYP1B1;68035,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Based on these findings, we conclude that, unlike LQTS-associated mutations, the @GENE$-@VARIANT$ variant does not severely affect the function of the channel. 2.3.2. KCNH2-p.C108Y Exhibits a Dominant-Negative Loss-of-Function Heterologous expression studies demonstrated that @GENE$-@VARIANT$ is a non-functional channel (Figure 4A).",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 @VARIANT$, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, @VARIANT$ was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of @GENE$ (Supplemental Material, Fig. S3).",5966321,DVL3;20928,PTK7;43672,p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,0
"@VARIANT$ and G213 are conserved residues through these organisms and located on conserved 2D fragments. Mutations of the residues could affect the function of the human WNT10A protein. In the case of R171C mutations, the substitution of Cys, a hydroxylic amino acid with a side chain shorter than Arg, might eliminate the electrostatic interaction of R171 with adjacent residues. The mutation G213S is expected to abolish the hydrophobic interaction of G213 with adjacent residues. Sequences of orthologs and predicted 2D structure of human @GENE$ protein. (A) The alignment of orthologs of the human WNT10A protein. The R171 and G213 residues are represented by arrowheads. (B) The predicted 2D structure of human WNT10A protein. The R171 and G213 residues are in yellow. The 3D structure of @GENE$ is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. I312 is located at the outer surface of the three monomers. An @VARIANT$ mutation could affect the interactions of EDA with its receptors.",3842385,WNT10A;22525,EDA;1896,R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555,I312M;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: @VARIANT$, p.Thr1100Met) and MUTYH (NM_001128425.1: c.536A > G, @VARIANT$) genes, while the other 20 genes could not be clearly linked to cancer predisposition. The identified MSH6 variant was classified as a variant of uncertain significance (VUS) in the Leiden Open Variant Database and the InSiGHT DNA Variant Database. 14 ,  15 The MUTYH variant is the most common pathogenic variant found in the Netherlands. 2                       The digenic inheritance of MSH6 and @GENE$ variants. A, The pedigree shows the coinheritance of the monoallelic variants which encode MSH6 p.Thr1100Met and MUTYH p.Tyr179Cys in a family affected by colorectal cancer. All spouses were unrelated and unaffected by cancer. Genotypes: @GENE$ p.Thr1100Met (T1100M; blue); MUTYH p.Tyr179Cys (Y179C; green); -, wild type.",7689793,MUTYH;8156,MSH6;149,c.3299C > T;tmVar:c|SUB|C|3299|T;HGVS:c.3299C>T;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0
"To date, a single @GENE$ mutation (@VARIANT$) is known to cause a late-onset myopathy with rimmed vacuoles (MRVs). TIA1 mutations were recently detected in amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), but a subsequent study suggested exerting caution on the causality of the TIA1 variants in ALS. Sequestosome-1 (SQSTM1, chr.5) is a scaffolding protein involved in multiple cellular processes, including apoptosis, cell survival, and autophagy. Its numerous domains allow SQSTM1 to serve as a frame for multiprotein complexes and regulator of ubiquitinated protein turnover. SQSTM1 mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single @GENE$ mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient.",5868303,TIA1;20692,SQSTM1;31202,p.Glu384Lys;tmVar:p|SUB|E|384|K;HGVS:p.E384K;VariantGroup:7;CorrespondingGene:7072;RS#:747068278;CA#:1697383,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Three variants in three genes were rare, including the PROKR2 gene mutation [p.(Lys205del)], a novel heterozygous missense variant [@VARIANT$; p.(@VARIANT$)] in the @GENE$ gene (NM_001146029), as well as a splice site variation in the @GENE$ gene (NM_032242; MAF = 0.03 in GnomAD).",8446458,SEMA7A;2678,PLXNA1;56426,c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"25  The @GENE$ (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS.",7689793,RYR3;68151,TRIP6;37757,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"To the best of our knowledge, two of the identified variants (FOXC2: @VARIANT$, p.(H395N); and PITX2: @VARIANT$, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and p.(H395N); PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, @VARIANT$ or Q446R (Supplementary Fig. 5a, b). On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,ENG;92,SCUBE2;36383,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, @VARIANT$), @GENE$ (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, @VARIANT$, p.Arg896Trp), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; @VARIANT$); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Novel Missense Mutation in the @GENE$ Gene in a Patient with Early Onset Ulcerative Colitis: Causal or Chance Association? Deregulated immune response to gut microflora in genetically predisposed individuals is typical for inflammatory bowel diseases. It is reasonable to assume that genetic association with the disease will be more pronounced in subjects with early onset than adult onset. The nucleotide-binding oligomerization domain containing-2 gene, commonly involved in multifactorial risk of Crohn's disease, and interleukin 10 receptor genes, associated with rare forms of early onset inflammatory bowel diseases, were sequenced in an early onset patient. We identified a novel variant in the NOD2 gene (c.2857A > G @VARIANT$) and two already described missense variants in the @GENE$ gene (@VARIANT$ and G351R).",3975370,NOD2;11156,IL10RA;1196,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"We detected a de novo Microphthalmia-associated transcription factor (MITF) (NM_000248) variant, @VARIANT$, in one of the c.235delC carriers (SH107-225) (Figure 4A). She inherited @VARIANT$ of @GENE$ from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). The p.R341 residue of MITF is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/@GENE$ and GJB2/GJB3 (group II).",4998745,GJB2;2975,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
"No mutations in @GENE$, TPO, or @GENE$ gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,SLC5A5;37311,IYD;12352,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and @GENE$ (@VARIANT$). Her father carries the mutations in @GENE$ and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,USH2A;66151,MYO7A;219,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"We identified four genetic variants (@GENE$-p.R583H, KCNH2-p.C108Y, @GENE$-@VARIANT$, and KCNE1-@VARIANT$) in an LQTS family.",5578023,KCNQ1;85014,KCNH2;201,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB2;2975,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Only three variants were homozygous in three patients: (1) @GENE$: c.2779A>G (p.M927V) in one patient, (2) DUOX2:@VARIANT$ (p.R1110Q) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,c.3329G>A;tmVar:c|SUB|G|3329|A;HGVS:c.3329G>A;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"These mutations are expected to affect the three classes of @GENE$ isoforms (Tables 2, 3, Figure 1). Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A), a novel nucleotide deletion (@VARIANT$; @VARIANT$), and six missense mutations, four of which (p.R1189W, p.R1379P, p.D2639G, and p.R3043W) had not been previously reported.",3125325,harmonin;77476,CDH23;11142,c.6404_6405delAG;tmVar:c|DEL|6404_6405|AG;HGVS:c.6404_6405delAG;VariantGroup:207;CorrespondingGene:65217,p.E2135fsX31;tmVar:p|FS|E|2135||31;HGVS:p.E2135fsX31;VariantGroup:3;CorrespondingGene:64072;RS#:55947063,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"(C) The @GENE$ mutation c.252DelT and WNT10A mutation @VARIANT$ were found in patient S1, who inherited the mutant EDA allele from his mother; WNT10A mutations in the parents could not be analyzed. (D) The EDA mutation c.457C>T and @GENE$ mutation c.637G>A were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis. (E) The EDA mutation c.466C>T and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in EDA and c.511C>T in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,0
"Conclusions Our results demonstrated that the loss-of-function @GENE$-@VARIANT$ mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,SPTBN4;11879,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"We identified four genetic variants (@GENE$-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas @GENE$-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-@VARIANT$ were previously reported to produce more severe phenotypes when combined with disease-causing alleles.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Thirteen (72.2%) of 18 patients were identified eleven variants in eight known causative genes, namely AXL receptor tyrosine kinase (AXL), coiled-coil domain containing 141 (CCDC141), chromodomain helicase DNA binding protein 7 (CHD7), Dmx like 2 (DMXL2), @GENE$ (FGFR1), patatin like phospholipase domain containing 6 (@GENE$), RNA polymerase III subunit A (POLR3A) and prokineticin receptor 2 (PROKR2), see (Table 1 and 2). The PROKR2 missense variant p. Trp178Ser was recurrently observed in three patients, and was statistically enriched in our IHH cohort compared to the population (3/18 in the IHH cases vs 56/9976 in the gnomAD East Asians, P = 0.00015, one-tailed Fisher's exact test). Furthermore, another PROKR2 missense variant @VARIANT$ was identified in case P15. All of the remaining deleterious variants in the other seven known IHH genes were novel and unreported. Notably, the novel LoF variant FGFR1 @VARIANT$ in case P05 is de novo and evaluated as pathogenic.",8152424,fibroblast growth factor receptor 1;69065,PNPLA6;21333,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and @GENE$ were found in two or more independent pedigrees.",6081235,MYOD1;7857,MRPL15;32210,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB6;4936,GJB2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,SPG11;41614,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,1
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The novel truncated variant in @GENE$ was not found in our ""in-house"" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The c.229C>T (@VARIANT$) variant in @GENE$ and c.238-241delATTG (@VARIANT$) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.",6637284,S100A13;7523,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,gap junction protein beta 6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,CCNF;1335,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"In this family, the patient (II: 1) with digenic heterozygous mutations of @GENE$ p.307_308del and @GENE$ @VARIANT$ presented the earliest phenotype of LQTS, and she suffered from syncope, torsades de pointes, and ventricular fibrillation more frequently at rest, whereas the members (I:1 and II:2) without KCNH2 @VARIANT$ showed normal QT intervals and cardiac function.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in @GENE$ was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2).",7549550,MYOD1;7857,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"In addition, a smaller band of ~75 kDa was observed for @GENE$. Thus, the @VARIANT$ SEC23A mutation does not modulate levels of @GENE$. However, the @VARIANT$ MAN1B1 mutation results in decreased levels of MAN1B1 in homozygous patients as well as in unaffected carriers.",4853519,MAN1B1;5230,SEC23A;4642,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"    A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (@VARIANT$; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, was identified in patient #3. BBS1, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of @GENE$ and @GENE$ lie in this portion.",6567512,BBS2;12122,BBS7;12395,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, DUOX2, DUOXA2 and @GENE$).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B).",7248516,SLC26A4;20132,TPO;461,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ @GENE$ and @VARIANT$ @GENE$ (figure 3D).",7279190,FLNB;37480,OFD1;2677,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,1
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a).",8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Coincidentally, PFBC patients with variants in both a PFBC pathogenic gene (SLC20A2 or PDGFRB) and another PFBC-unrelated gene (@GENE$, CHRNB2, @GENE$, SCN2A or MEA6) were described as presenting more complex phenotypes, supporting the notion that a variant of a second gene may promote a heterogeneous phenotype in PFBC patients (Baker et al., 2014; Borges-Medeiros & de Oliveira, 2020; DeMeo et al., 2018; Fjaer et al., 2015; Fujioka et al., 2015; Knowles et al., 2018). The SLC20A2 @VARIANT$ (p.His596Arg) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the PDGFRB @VARIANT$ (p.Arg106Pro) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,THAP1;10005,CASR;332,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and @VARIANT$, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father).",3975370,IL10RA;1196,NOD2;11156,c.1051A > G;tmVar:c|SUB|A|1051|G;HGVS:c.1051A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,1
"This sequence variant changes a glutamine codon (CAG) to a translation termination codon (TAG) at position 1252 (NP_002327.2:@VARIANT$) and will likely subject the altered transcript to nonsense mediated decay. The mutation is not documented in the Genome Aggregation Database (gnomAD) or the Taiwan BioBank database. In addition, a missense sequence variant in WNT10A (NG_012179.1:@VARIANT$; NM_025216.3:c.338G>A; NP_079492.2:p.Arg113His) was also identified (Figure S1A). This variant, designated as rs749324327, has a minor allele frequency (MAF) of ~0.0004 in East Asian (EAS) populations and is predicted to be ""benign"", with a PolyPhen-2 score of 0.015. No potential pathogenic mutations were detected in other candidate genes of FTA. Further Sanger sequencing and segregation analysis indicated that the @GENE$ and @GENE$ mutations were both inherited from the father.",8621929,LRP6;1747,WNT10A;22525,p.Gln1252*;tmVar:p|SUB|Q|1252|*;HGVS:p.Q1252*;VariantGroup:15;CorrespondingGene:4040,g.6853G>A;tmVar:g|SUB|G|6853|A;HGVS:g.6853G>A;VariantGroup:3;CorrespondingGene:80326;RS#:749324327;CA#:2113880,1
"Since the @GENE$ @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,FGFR1;69065,DCC;21081,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/@GENE$ binding, thus stimulating VEGF signalling (figure 3). The @VARIANT$ (@VARIANT$) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies.",6161649,VEGFR2;55639,SCUBE2;36383,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"He also had a @GENE$ deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with @GENE$/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of @GENE$ and C104R (c.310T>C) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Case 2 revealed a novel, heterozygous @VARIANT$ (c.5560C>G; p.Ser1887Cys) of the LDL receptor-related protein 4 (LRP4) gene (OMIM 604270). This gene variant was also found in the mother and the maternal uncle. In case 3, a heterozygous change of cytosine to thymine was found at location 1660 of the LHCGR gene (OMIM 152790). This mutation changes codon 554 from arginine to a stop codon (@VARIANT$; p.Arg554Stop) and has been previously reported. The mother did not carry this @GENE$ (LHCGR) mutation. In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified @GENE$ variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the AMH, SRY, and CYP17 promoters.",5893726,luteinizing hormone/choriogonadotropin receptor;37276,GATA4;1551,C to G change at position 5660;tmVar:g|SUB|C|5660|G;HGVS:g.5660C>G;VariantGroup:2;CorrespondingGene:4038;RS#:73460019;CA#:221665112,c.1160C>T;tmVar:c|SUB|C|1160|T;HGVS:c.1160C>T;VariantGroup:1;CorrespondingGene:2626;RS#:368991748;CA#:172121374,0
"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ @VARIANT$ (p.M400I) and @GENE$ c.1000C>T (@VARIANT$), associated with congenital birth defects in two patients from a consanguineous family.",4853519,SEC23A;4642,MAN1B1;5230,c.1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,p.R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,ubiquilin-2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Nonsynonymous mutations in @GENE$ were found in 24 patients (20 males and 4 females), all in heterozygous state (Table 1). They consist of a frameshifting deletion of 14 nucleotides (c.del1613_1626; @VARIANT$), and seven different missense mutations (p.R66W, p.N153S, p.I400V, p.V435I, p.T688A, @VARIANT$, p.R733H) that affect evolutionarily conserved aminoacid residues located in different domains of the protein (Figure 3). In addition, the p.R730Q and p.R733H mutations, which both remove basic residues in the C-terminal basic motif of Sema3A, are predicted to affect in vivo proteolytic processing by @GENE$-like endoproteases at residue R734.",3426548,SEMA3A;31358,furin;1930,p.D538fsX31;tmVar:p|FS|D|538||31;HGVS:p.D538fsX31;VariantGroup:12;CorrespondingGene:2260,p.R730Q;tmVar:p|SUB|R|730|Q;HGVS:p.R730Q;VariantGroup:2;CorrespondingGene:10371;RS#:318240752;CA#:220074,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Two novel variants were identified in @GENE$, including one frameshift mutation (@VARIANT$, p.C687LfsX34) and one missense mutation (c.1514G>A, @VARIANT$). A novel missense mutation was found in @GENE$ (c.398G>A, p.R133H).",6098846,TG;2430,DUOXA2;57037,c.2060_2060delG;tmVar:c|DEL|2060_2060|G;HGVS:c.2060_2060delG;VariantGroup:68;CorrespondingGene:405753,p.G505D;tmVar:p|SUB|G|505|D;HGVS:p.G505D;VariantGroup:10;CorrespondingGene:7173;RS#:867829370,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the @GENE$ and @GENE$ proteins lead us to hypothesize that digenic variants in NRXN1 and NRXN2 contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"c, d Immunoprecipitation of @GENE$ with mutated pendrin. Immunocomplex of myc-@GENE$ L117F, @VARIANT$ and @VARIANT$ was not affected.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,CACNA1A;56383,MYOD1;7857,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: @VARIANT$ (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"We suggest that: 1) the PKD2 p.(@VARIANT$) variant is pathogenic, since it is de-novo in a patient with a renal cystic disease and is transmitted to both fetuses; 2) the p.(Ser123Thr) variant in PKD1 is hypomorphic, since it does not cause renal disease in the father (age 44 years), but worsens the renal phenotype when co-inherited with a PKD2 mutation; 3) the missense variant p.(@VARIANT$) in PKD2, already described as disease-causing in HGMD database (Neumann et al.,), is likely benign, since it is present in a healthy man and does not segregate with disease in the fetuses. Pedigree of Family 18287 with bilineal inheritance of @GENE$/@GENE$ variants.",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,ubiquilin-2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"For example, two variants in proband P15, @VARIANT$ in @GENE$ and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively.",8152424,PROKR2;16368,CHD7;19067,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,0
"These include complete conservation of @VARIANT$ (Figures S1-S4), SIFT analysis, and protein modeling. Furthermore, protein expression was markedly reduced in vitro, providing additional support for a deleterious effect. This patient with the p.Ala253Thr NELF missense mutation also had a hemizygous KAL1 deletion of the completely conserved @VARIANT$ within the whey-acidic-protein (WAP) domain that forms a disulphide bridge with Cys134 of anosmin-1 (Figure S1C,D). Unilateral renal agenesis in this patient is likely related to this deleterious KAL1 mutation. The third KS male was heterozygous for both @GENE$ and @GENE$ nonsense mutations.",3888818,NELF;10648,TACR3;824,Ala253;tmVar:p|Allele|A|253;VariantGroup:3;CorrespondingGene:26012;RS#:142726563,Cys163;tmVar:p|Allele|C|163;VariantGroup:9;CorrespondingGene:3730,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), @GENE$ (@VARIANT$; p.L16V) and @GENE$ (c.9921T>G).",3125325,USH1G;56113,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"These two individuals were heterozygous carriers of @VARIANT$ mutation in @GENE$ and @VARIANT$ in @GENE$. Since heterozygous carriers of p.R1141X in ABCC6 alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and @GENE$ has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).",7549550,RIPPLY1;138181,MYOD1;7857,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"Notably, our patient's @GENE$ variant, p.P340S, is three amino acids away from a well-documented class IB mutation @VARIANT$, supporting the hypothesis that this novel SOS1 variant is contributing to her phenotype. The @VARIANT$ mutation in @GENE$ has been associated with fetal macrosomia in one individual (Table I).",5101836,SOS1;4117,PTPN11;2122,p.Y337C;tmVar:p|SUB|Y|337|C;HGVS:p.Y337C;VariantGroup:0;CorrespondingGene:6654;RS#:724160007;CA#:90930,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,0
"Furthermore, this CACNA1C-@VARIANT$ mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (p.R1193Q, @VARIANT$) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This SCN5A-R1193Q variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).    Gene variants of @GENE$ and @GENE$ identified in the family.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,rs41261344;tmVar:rs41261344;VariantGroup:7;CorrespondingGene:6331;RS#:41261344,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,DVL3;20928,PTK7;43672,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"In addition to inherited disease, a recent report of monozygotic twins discordant for CVID, demonstrated differential methylation signatures of @GENE$ between the unaffected and affected twins. The authors postulated impaired activity of TCF3/E2A accounted for the presence of disease. Two independent studies of gene-targeted mice with TCF3 haploinsufficiency have shown reduced numbers of B cells and impaired lymphoid cell development. Similarly, reduced expression of TCF3/E2A has been implicated in equine CVID. There is thus strong support from human, murine and equine studies for the pathogenicity of the TCF3 @VARIANT$ mutation in our family. Our study also offers new insights into the role of TNFRSF13B/TACI mutations in the pathogenesis of CVID. The @VARIANT$ mutant is a low frequency variant in population databases (0.32% in Exome Aggregation Consortium) and although earlier publications considered this variant to be disease-causing and expressed in up to 10% of CVID patient cohorts, it, and other @GENE$/TACI variants were subsequently found to be present in ~2% of healthy control populations.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; @VARIANT$) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,USH1G;56113,MYO7A;219,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, @VARIANT$, was identified in patient #3. BBS1, @GENE$ and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS2;12122,BBS7;12395,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0
"In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in ENG by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,ENG;92,VEGFR2;55639,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB3;7338,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"  Digenic inheritances of GJB2/MITF and @GENE$/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus.",4998745,GJB2;2975,GJB6;4936,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ FLNB and @VARIANT$ @GENE$ (figure 3D).  @GENE$ and OFD1 variants in individuals with AIS. (A) Pedigree of AIS twins.",7279190,OFD1;2677,FLNB;37480,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,DNAH17;72102,MRPL15;32210,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,ATP2A3;69131,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Moreover, the presence of other variants (KCNQ1-@VARIANT$, @GENE$-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ @VARIANT$, SCRIB @VARIANT$, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, @VARIANT$), @GENE$ (NM_018328.4, c.2000T>G, @VARIANT$), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$).",6610752,LQT2;201,LQT6;71688,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: @VARIANT$ and p.(H395N); PITX2: @VARIANT$). In summary, the increased frequency in PCG patients of rare FOXC2 and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and @VARIANT$ (p.Asn118Ser) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a @VARIANT$ of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"                  In this study, we identified nine reported gene variants, and we detected 13 novel variants: @VARIANT$(p. Ser509fs) and c.1524del A(p. Ser509fs) variants in the KAl1 gene; c.223 - 4C > A and c.306G > C(p. Arg102Ser) variant in the PROK2 gene: c.963dup A (p. Glu322fs), c.1695_1696insT(p. Lys566Ter), c.580G > T(p. Gly194Cys), c.1886 T > C(p. Val629Ala), c.2147G > T(p. Gly716Val), @VARIANT$, c.1974_ 1977del (p. Asn659fs), and c.75_ 78del (p. Thr26fs) variants in the @GENE$ gene; and c.875 T > C (p. Ile292Thr) variant in the @GENE$ gene.",8796337,FGFR1;69065,SEMA3A;31358,c.1525del A;tmVar:c|DEL|1525|A;HGVS:c.1525delA;VariantGroup:13;CorrespondingGene:3730,c.1081 + 1del;tmVar:c|DEL|1081+1|;HGVS:c.1081+1del;VariantGroup:25;CorrespondingGene:2260,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Although the majority of @GENE$ mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging.       In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel @VARIANT$ deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The NEK1 R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with @GENE$ variants (L106V and @VARIANT$).",6707335,FUS;2521,CCNF;1335,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Sequencing of Case 7 revealed a heterozygous c.1183_1185delGAG non-frameshift variation in exon 7 that leads to the @VARIANT$ (p.Glu395del) in the LBD of the protein. This variant was also found in the mother of the patient. Except for Case 4, DNA samples of patients, in which only a single gene approach had been performed initially, were further analyzed by the targeted DSD gene panel including 48 genes. Additional heterozygous variants in known DSD genes were found in three out of six (50%) 46,XY DSD NR5A1 carriers. For Case 1, a novel missense VUS (variant of unknown significance) variant (c.361C>T; p.Arg121Trp) in the @GENE$ gene was identified in the patient and his father. A rare variant in AMH, c.428C>T; @VARIANT$, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported @GENE$/FOG2 (c.1632G>A; p.Met544Ile) pathogenic missense alteration was identified.",7696449,STAR;297,ZFPM2;8008,deletion of amino acid 395;tmVar:|DEL|395|OF;HGVS:c.395delOF;VariantGroup:6;CorrespondingGene:1113,p.Thr143Ile;tmVar:p|SUB|T|143|I;HGVS:p.T143I;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,0
"The proband, his mothor and one brother carried a heterozygous @VARIANT$ transition in exon 20, which results in an alanine to a serine (Ala771Ser) in @GENE$. Another variation, @VARIANT$ in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,2311G>T;tmVar:c|SUB|G|2311|T;HGVS:c.2311G>T;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,1
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and @GENE$. Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C TTC26 proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ FLNB proteins, respectively (figure 2D, E).",7279190,FLNB;37480,TTC26;11786,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,0
KCNH2 @VARIANT$ may affect the function of @GENE$ channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. @GENE$ p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and SCN5A @VARIANT$ by WES and predisposing genes analyses.,8739608,Kv11.1;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
The PITX2 variant @VARIANT$ did not show significant protein stability differences with the wild-type protein (Fig 6C and Fig 6D). FOXC2 @VARIANT$ variant decreases protein stability. Time course stability analysis of @GENE$ (A) and @GENE$ (C) coding variants found in PCG patients was carried out by transient expression in HEK-293T cells.,6338360,FOXC2;21091,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.H395N;tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"A single @GENE$ mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"The minimum free energy (MFE) of @GENE$ @VARIANT$ increased, which thus led to a reduction of structural stability. (c, d) @GENE$ @VARIANT$ showed no significant influence on the RNA structure, and the MFE value of SCN5A p.R1865H mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, p. A85P, @VARIANT$, p.F112S, p.R127L, @VARIANT$, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,p.G149D;tmVar:p|SUB|G|149|D;HGVS:p.G149D;VariantGroup:15;CorrespondingGene:1805;RS#:777651623,0
"Furthermore, this @GENE$-@VARIANT$ mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (@VARIANT$, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in @GENE$ was also found in the proband (Fig 2D, Table 2).",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant @VARIANT$. The @GENE$ gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,DUSP6;55621,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
"II: 1 carried the digenic heterozygous mutations of KCNH2 @VARIANT$ and @GENE$ p.R1865H. I: 1 and II: 2 were heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry @GENE$ mutation.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"Sequence alterations were detected in the COL6A3 (rs144651558), RYR1 (rs143445685), CAPN3 (@VARIANT$), and DES (@VARIANT$) genes. These variants were then screened in his sister who had inherited all variants except that found in the @GENE$ gene. The @GENE$ and RYR1 variants were predicted to be benign by SIFT and PolyPhen and MutationTaster analysis.",6180278,CAPN3;52,COL6A3;37917,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,ubiquilin-2;81830,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Another candidate variant in @GENE$ (@VARIANT$) did not completely cosegregate with dystonia in this pedigree (Table S2, Data S1). Moreover, expression of MYH13 is mainly restricted to the extrinsic eye muscles. A nonsense variant in @GENE$ (NM_000625.4: c.2059C>T, @VARIANT$; CADD_phred = 36) was shared by the two affected individuals analyzed with WES but NOS2 is expressed at only low levels in brain and Nos2 -/- mice have not been reported to manifest positive or negative motor signs.",6081235,MYH13;55780,NOS2;55473,rs7807826;tmVar:rs7807826;VariantGroup:17;RS#:7807826,p.Arg687*;tmVar:p|SUB|R|687|*;HGVS:p.R687*;VariantGroup:55;CorrespondingGene:18126,1
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in @GENE$ (p.N382S/@VARIANT$) and MYO6 (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,MYO6;56417,GFI1;3854,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"The latter individuals were also carriers of the @GENE$ nonsense mutation p.R1141X. Specifically, the mother and her twin sister were heterozygous for the @GENE$ missense mutation @VARIANT$ and the ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings.",2900916,ABCC6;55559,GGCX;639,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"In the subject III.1, the variant, carried in the heterozygous status, is the @VARIANT$; p.Glu290*, in the @GENE$ (@GENE$) gene; the III.2 subject carried the @VARIANT$; p.Pro291Arg, in the HNF1A gene.",8306687,glucokinase;55440,CGK;55964,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,UBQLN2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Four genes (including @GENE$, ZFHX3, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only @GENE$-c.3035C>T (@VARIANT$) and AGXT2-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,AGXT2;12887,SCAP;8160,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"Quantification of cells with dilated endoplasmic reticulum (ER) and COPII vesicles associated with Golgi by transmission electron microscopy Genotype of cell line Cells with dilated ER (%) Cells with Golgi-associated vesicles (%) Wt (N = 414) 2 (0.5) 309 (75) SEC23Ac.1200G>C/+ (N = 83) 83 (100***) 9 (11***) SEC23Ac.@VARIANT$/+ MAN1B1@VARIANT$/+ (N = 190) 190 (100***) 3 (1.6***) SEC23Ac.1200G>C/c.1200G>C; MAN1B1c.1000C>T/c.1000C>T (N = 328) 328 (100***) 2 (0.6***)  Increased Intracellular and Secreted Pro-COL1A1 in Fibroblasts with Homozygous Mutations in Both @GENE$ and @GENE$ in the Presence of l-Ascorbic Acid SEC23A is required for normal transport of pro-COL1A1, a major extracellular matrix component of bone.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"@VARIANT$ was the most common mutation identified in our patient cohort, which differed from previous reports in Korean (p.G488R) and Japanese (p.R855Q) populations. Additionally, p.K530X was the most common mutation identified in Chinese patients from southern or central China. Besides DUOX2, TG anomalies are another common cause of DH. However, in the present study, four detected TG variants presented separately in four different patients with heterozygosity and always cooccurred with variants in @GENE$ or other DH-related genes, indicating that the contributions of TG mutations to DH in Xinjiang Han Chinese might be less important. More CH-associated @GENE$ mutations were found recently. Our study identified two known truncating variants, p.Y246X and p.Y138X, which cooccurred in a patient with permanent CH. A previous study first noted @VARIANT$ homozygosity in a patient with mild permanent CH and dyshormonogenic goiter, and compound heterozygosity with p.Y138X and p.Y246X was reported in another patient.",6098846,DUOX2;9689,DUOXA2;57037,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.Y246X;tmVar:p|SUB|Y|246|X;HGVS:p.Y246X;VariantGroup:8;CorrespondingGene:90527;RS#:4774518;CA#:114294,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(Cys331Thr) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(@VARIANT$).",7224062,PKD1;250,PKD2;20104,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,1
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous DUOX2 nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of @GENE$ (c.1823-1G>C) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1 and -2;53905;50506,DUOX1;68136,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; @VARIANT$, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,g.112084C>G;tmVar:g|SUB|C|112084|G;HGVS:g.112084C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"These two individuals were heterozygous carriers of p.R1141X mutation in ABCC6 and @VARIANT$ in GGCX. Since heterozygous carriers of p.R1141X in ABCC6 alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance. In this case, haploinsufficiency of the carboxylase activity and reduced ABCC6 functions could be complementary or synergistic. The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (@VARIANT$) and the @GENE$ gene (p.S300F) yet did not display any cutaneous findings are not clear.",2900916,ABCC6;55559,GGCX;639,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
We identified a novel variant in the NOD2 gene (c.@VARIANT$ p.K953E) and two already described missense variants in the @GENE$ gene (@VARIANT$ and G351R). The new @GENE$ missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation.,3975370,IL10RA;1196,NOD2;11156,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"There is a splicing site mutation @VARIANT$ in COL4A5, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
The KCNQ1-@VARIANT$ variant was previously reported to be associated with LQTS; KCNH2-@VARIANT$ is a novel variant; and KCNH2-p.K897T and KCNE1-p.G38S were reported to influence the electrical activity of cardiac cells and to act as modifiers of the @GENE$ and @GENE$ channels.,5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"The following genes showed variants in two patients: @GENE$ in patients 1 and 6; EVC in patients 1 (2 variants) and 7; IRX5 in patients 5 and 6; MAML1 in patients 4 and 6; MAML2 in patients 5 and 8; NOTCH2 in patients 5 and 7; RECQL4 in patients 2 and 3 and @GENE$ in patients 6 and 7 ( Table 2 ). In addition, 2 genes presented variants in 3 patients: MAML3 (patients 6, 7 and 8) and NOTCH1 (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,CYP1A1;68062,WDR11;41229,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Moller et al. reported an index case with digenic variants in MYH7 (L1038P) and MYBPC3 (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in @GENE$ (@VARIANT$) and @GENE$ (Asn83His), both sarcomeric genes.",6359299,MYH7;68044,TNNT2;68050,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773,0
"The two additional subjects could each be compound heterozygotes comprised of a rare variant (@VARIANT$ or p.I2547T with 0.3% and 0.5% MAF in population database respectively) and a novel variant (p.R168Q or @VARIANT$ respectively). The subject carrying p.I2547T and p.T14I was also heterozygous for @GENE$ p.R408C which has previously been reported in a subject with SALS. Due to the absence of additional family members for segregation or tissue for cDNA sequencing, we were unable to determine if these SETX variants are in cis or trans. Because recessive mutations in @GENE$ are associated with ataxia-ocular apraxia type 2 (OMIM 606002) and SETX-associated ALS is dominantly inherited, we reviewed the medical records of these 3 individuals.",4293318,TAF15;131088,SETX;41003,p.C1554G;tmVar:p|SUB|C|1554|G;HGVS:p.C1554G;VariantGroup:31;CorrespondingGene:23064;RS#:112089123;CA#:5297159,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in ENG by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling.",6161649,MAP4K4;7442,SCUBE2;36383,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant p.(Lys205del). The @GENE$ gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,DUSP6;55621,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
"Functional characterization of GATA4 variants with respect to the 46,XY DSD phenotype has only been performed for the @VARIANT$ mutation so far. In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the AMH promoter, and failed to bind cofactor @GENE$. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation p.Cys238Arg, but no effect on transactivation activity on the CYP17 promoter for GATA4 variants p.Pro226Leu and p@VARIANT$. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only Gly221 and Cys238 are close to Zn binding sites. The Gly221 is not directly involved in Zn binding but is situated next to Cys220 which binds the Zn atom, and therefore, the mutation Gly221Arg will disrupt the Zn binding, leading to a non-functional @GENE$. The Cys238 binds Zn and its mutation to arginine leads to loss of Zn binding (Figure 4).",5893726,FOG2;8008,GATA4;1551,p.Gly221Arg;tmVar:p|SUB|G|221|R;HGVS:p.G221R;VariantGroup:4;CorrespondingGene:2626;RS#:398122402(Expired),Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  @GENE$, 23  @GENE$, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, @VARIANT$) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS.",7689793,EBNA1BP2;4969,TRIP6;37757,p.Asn2604Lys;tmVar:p|SUB|N|2604|K;HGVS:p.N2604K;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and @VARIANT$ (c.310T>C) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ @VARIANT$ mutation, but not the TNFRSF13B/TACI C104R mutation.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Similarly, the @GENE$-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (@GENE$)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,CCDC88C;18903,DCC;21081,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of USH2A (NM_007123), @VARIANT$, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and @GENE$ (ANK1) identified in SH 94-208).",4998745,USH2A;66151,Ankyrin 1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,R5143C;tmVar:p|SUB|R|5143|C;HGVS:p.R5143C;VariantGroup:6;CorrespondingGene:7399;RS#:145771342;CA#:182576,0
"None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:@VARIANT$; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).                   The @GENE$ variant [NM_033056: c.3101G > A; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892).",6053831,USH1G;56113,PCDH15;23401,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,72915838C > T;tmVar:g|SUB|C|72915838|T;HGVS:g.72915838C>T;VariantGroup:1;CorrespondingGene:124590;RS#:538983393;CA#:8753931,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a @GENE$ (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.",5505202,WDR11;41229,EMX1;55799,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2). While TIMP3 blocks VEGF/VEGFR2 signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,ENG;92,RASA1;2168,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"(E) The @GENE$ mutation @VARIANT$ and @GENE$ mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in EDA and @VARIANT$ in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The recurrent mutation @VARIANT$ was found in the DNA from the father, mother, the maternal aunt and the younger brother, but not in the proband herself or her sister. In addition, no other ABCC6 mutations could be disclosed in this family. Considering the clinical finding of coagulation disorder of the proband and her sister, we also sequenced the GGCX and VKORC1 genes, in which mutations cause the type I and type II vitamin K-dependent coagulation factor deficiency disorders, respectively. Sequencing of the @GENE$ gene revealed two distinct missense mutations in this family, and specifically, mutations p.V255M in exon 7 and @VARIANT$ in exon 8 of the GGCX gene were identified. The proband and her sister were compound heterozygotes for the two GGCX missense mutations, while the proband's father, brother, her mother and maternal aunt were heterozygous for one of the GGCX mutations only (Fig. 1g). Sequencing of the whole coding region of @GENE$ gene did not reveal any pathogenic mutation.",2900916,GGCX;639,VKORC1;11416,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0
"Compound heterozygous variants in DSCAML1, @GENE$ and @GENE$ were retained. In two unrelated patients, AVM106 and AVM285, identical compound heterozygous variants were identified in DSCAML1: c.5783G>A (p.Arg1928His) and c.4574G>A (p.Arg1525His), each inherited from heterozygous carrier parents (table 2). Both variants were reported in ExAC with an allele frequency <0.001, and they were predicted in silico to be highly deleterious (GERP++>4 and CADD>30 for both). In patient AVM226, we identified the compound heterozygous variants c.3775G>A (@VARIANT$) and c.2966A>T (@VARIANT$) in DSCAM (table 2).",6161649,DSCAM;74393,PTPN13;7909,p.Val1259Ile;tmVar:p|SUB|V|1259|I;HGVS:p.V1259I;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,p.Gln989Leu;tmVar:p|SUB|Q|989|L;HGVS:p.Q989L;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"The results of our study and the @GENE$ study consistently suggested that the rate of oligogenic inheritance of IHH genes varies and maintains at high levels. According to our data, eight patients had at least two IHH gene variants. Two patients carried three variants and one patient even carried four variants. Our data supported ""additive effect"" and ""cumulative mutation burden"" that were proposed in studies related to IHH. For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 @VARIANT$ and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively.",8152424,PLXNA1;56426,CDON;22996,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, @VARIANT$, R165W, F191L, and A197S in Cx26 as well as F193C, S198F and G199R in Cx32, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the @GENE$ gene except for the EC2 and TM4 domains, which are main domains for deafness mutations. This correlation between location of mutations and phenotypes, together with the identification of pathological mutations associated with hearing loss in the same region of the EC2 and TM4 domains in these three connexin genes (Cx26, Cx31, and @GENE$) suggested that the EC2 and TM4 domains are important to the function of the Cx31 protein in the inner ear and plays a vital role in forming connexons in the cells of the inner ear. In the present study, we have shown that the missense @VARIANT$ and A194T mutations in GJB3 acts in a recessive manner in three unrelated Chinese patients.",2737700,Cx31;7338,Cx32;137,M163L;tmVar:p|SUB|M|163|L;HGVS:p.M163L;VariantGroup:7;CorrespondingGene:2706;RS#:80338949,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Sequence alterations were detected in the @GENE$ (rs144651558), @GENE$ (@VARIANT$), CAPN3 (rs138172448), and DES (@VARIANT$) genes.",6180278,COL6A3;37917,RYR1;68069,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,DNAH17;72102,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"All but 1 patient had a @GENE$ mutation in association with mutation(s) in different genes. A total of 2 novel variants, p.S309P and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different @GENE$ mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and @VARIANT$ were novel. @VARIANT$ is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and p.R528S and p.K618* are located in the cytoplasmic loops (Fig. S3C).",7248516,TPO;461,TSHR;315,p.K618;tmVar:p|Allele|K|618;VariantGroup:4;CorrespondingGene:7253,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,CELSR1;7665,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We identified four genetic variants (@GENE$-p.R583H, KCNH2-p.C108Y, KCNH2-@VARIANT$, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and @GENE$-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:@VARIANT$; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.",4470809,TBK1;22742,OPTN;11085,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,0
"Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/@GENE$-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"No significant change was observed with HA-TEK G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant @GENE$ and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and @VARIANT$ exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK.",5953556,CYP1B1;68035,TEK;397,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Case A was a compound heterozygote for mutations in @GENE$, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in @GENE$. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain.",4470809,OPTN;11085,TBK1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, @GENE$, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the @GENE$ gene variant [p.(@VARIANT$)].",8446458,PLXNA1;56426,DUSP6;55621,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,KCNE2;71688,LQT2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Circles: females; squares: males; white symbols: not included in the study; white symbols with genotype: unaffected; black symbols: pulmonary fibrosis affected; +: wild-type ""C"" allele of @GENE$/wild-type sequence of @GENE$; -: mutant ""T"" allele of S100A3 (@VARIANT$)/4 bp deletion of S100A13 (@VARIANT$).",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered @GENE$ without TES were found to be @GENE$, DFNB3, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES.",4998745,DFNB1;2975,DFNB7/11;23670,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in IMP4 (OMIM 612981; @VARIANT$, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in @GENE$ (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and @GENE$ (OMIM 612496; rs144638812, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,UBR4;10804,ARHGEF19;17710,rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,0
"Detection of mutations Screening of the WNT10A, EDA, EDAR, and EDARADD genes was performed by direct sequencing of five PCR fragments for WNT10A, eight PCR fragments for EDA, ten PCR fragments for @GENE$, and eight PCR fragments for EDARADD, which cover the entire cDNA including exons and intron-exon junctions of more than 100 base pairs. We compared all primer sequences to the whole-genome assembly in the ENSEMBL database to verify their uniqueness against gene families. Primer sequences are available upon request. Protein structure analysis We performed protein structure analysis on the two WNT10A mutations (p.R171C and @VARIANT$) and two novel @GENE$ mutations (@VARIANT$ and p.I312M) that were identified in this study.",3842385,EDAR;7699,EDA;1896,p.G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Three variants in three genes were rare, including the PROKR2 gene mutation [@VARIANT$], a novel heterozygous missense variant [@VARIANT$; p.(Glu436Lys)] in the @GENE$ gene (NM_001146029), as well as a splice site variation in the @GENE$ gene (NM_032242; MAF = 0.03 in GnomAD).",8446458,SEMA7A;2678,PLXNA1;56426,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750,0
"The mutations of KCNH2 @VARIANT$ and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous SCN5A @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a). Except II: 1, other family members without cardiac event or cardiac disease did not carry KCNH2 mutation. Moreover, the conservation analyses demonstrated that the mutant sites of amino acid sequences of @GENE$ and @GENE$ protein were highly conserved (Figure 2).",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"We finally found evidence of four potential novel candidate genes contributing to IHH: coiled-coil domain containing 88C (CCDC88C), cell adhesion associated, oncogene regulated (CDON), @GENE$ (GADL1), and sprouty related EVH1 domain containing 3 (SPRED3). The @GENE$ missense variant p. Arg1299Cys was heterozygous in case P05. CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant @VARIANT$ was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,glutamate decarboxylase like 1;45812,CCDC88C;18903,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,VAPB;36163,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (@VARIANT$).",5887939,SCRIB;44228,CELSR2;1078,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0
"The R171 and @VARIANT$ residues are represented by arrowheads. (B) The predicted 2D structure of human @GENE$ protein. The R171 and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The G257 residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. I312 is located at the outer surface of the three monomers. An @VARIANT$ mutation could affect the interactions of @GENE$ with its receptors.",3842385,WNT10A;22525,EDA;1896,G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216,I312M;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ E229K to immunoprecipitate HA-TEK E103D and HA-TEK @VARIANT$, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant @GENE$ proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2).",5953556,CYP1B1;68035,TEK;397,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Notably, our patient's SOS1 variant, p.P340S, is three amino acids away from a well-documented class IB mutation @VARIANT$, supporting the hypothesis that this novel @GENE$ variant is contributing to her phenotype. The @VARIANT$ mutation in @GENE$ has been associated with fetal macrosomia in one individual (Table I).",5101836,SOS1;4117,PTPN11;2122,p.Y337C;tmVar:p|SUB|Y|337|C;HGVS:p.Y337C;VariantGroup:0;CorrespondingGene:6654;RS#:724160007;CA#:90930,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,0
"Furthermore, @GENE$ presented 2 variants in patient 1. Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and @GENE$ variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,RIPK4;10772,MAML3;41284,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"We found eight probands (6.0%) who carried four rare @GENE$ variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare @GENE$ variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: @VARIANT$, p.(H395N); and PITX2: @VARIANT$, p.(P179T)) have not been previously identified.",6338360,FOXC2;21091,PITX2;55454,c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"By contrast, the expression of human @GENE$ and @GENE$, either alone or in combination, did not restore the viability of the mutant (Fig 3C), suggesting that the human orthologs have evolved in structure and function in comparison to Gcn5. As the mutated amino acid in KAT2B, @VARIANT$, is conserved in Drosophila Gcn5 (corresponding to Gcn5 F304), we re-expressed Gcn5 F304S in the Gcn5E333st hemizygous background (Gcn5 @VARIANT$).",5973622,KAT2A;41343,KAT2B;20834,F307;tmVar:p|Allele|F|307;VariantGroup:1;CorrespondingGene:8850,F304S;tmVar:p|SUB|F|304|S;HGVS:p.F304S;VariantGroup:6;CorrespondingGene:39431,0
"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, @GENE$, DCC, @GENE$, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)].",8446458,ANOS1;55445,PLXNA1;56426,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 @VARIANT$, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of @GENE$, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and @VARIANT$ was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,SCRIB;44228,CELSR1;7665,p.Q2924H;tmVar:p|SUB|Q|2924|H;HGVS:p.Q2924H;VariantGroup:1;CorrespondingGene:9620;RS#:200116798;CA#:10292663,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,CDON;22996,CCDC88C;18903,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(Ser123Thr), and a second variant in PKD2, p.(@VARIANT$).",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MEOX1;3326,TBX6;3389,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CACNA1A;56383,UNC13B;31376,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"  Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (@VARIANT$); P1, P2: thyrotropin >100 microU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (@VARIANT$) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred. Conclusion: This is a report of digenic mutations in @GENE$ and @GENE$ in association with CH, and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype.",5587079,DUOX1;68136,DUOX2;9689,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,1
"We suggest that: 1) the @GENE$ p.(@VARIANT$) variant is pathogenic, since it is de-novo in a patient with a renal cystic disease and is transmitted to both fetuses; 2) the p.(@VARIANT$) variant in @GENE$ is hypomorphic, since it does not cause renal disease in the father (age 44 years), but worsens the renal phenotype when co-inherited with a PKD2 mutation; 3) the missense variant p.(Arg872Gly) in PKD2, already described as disease-causing in HGMD database (Neumann et al.,), is likely benign, since it is present in a healthy man and does not segregate with disease in the fetuses.",7224062,PKD2;20104,PKD1;250,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,1
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered @GENE$ without TES were found to be DFNB7/11, DFNB3, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in @GENE$ (WFS1) (NM_001145853) according to TES.",4998745,DFNB1;2975,Wolfram syndrome 1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus lead to a reduction of structural stability. However, @GENE$ @VARIANT$ showed no significant influence on the RNA structure (Figure 4c,d). The MFE of SCN5A p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.           RNA secondary structural prediction. (a, b) Compared with wild-type KCNH2, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of @GENE$ p.307_308del increased, which thus led to a reduction of structural stability.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"The analysis included the complete coding regions and splice junctions of the following genes in the RAS-MAPK pathway: BRAF, HRAS, KRAS, MAP2K1, MAP2K2, PTPN11, @GENE$, and SOS1, as well as exon 2 of SHOC2. The DNA sequence was analyzed and compared to published genomic reference sequences. The result was confirmed by repeat sequence analysis on a newly prepared DNA sample. Multiple databases were queried to determine the novelty of the identified SOS1 variant, including a proprietary GeneDx database of previously tested patients, Human Gene Mutation Database, dbSNP, and NCBI/Pubmed. Also, the variant was analyzed using the missense variant pathogenicity prediction software SIFT (Sorting Intolerant From Tolerant; http://sift.bii.a-star.edu.sg/) and POLYPHEN (Polymorphism Phenotyping; http://genetics.bwh.harvard.edu/pph/). RESULTS Molecular genetic testing of the RAS/MAPK pathway revealed a known pathologic heterozygous mutation in exon 12 of PTPN11 (@VARIANT$) and a novel missense variant in @GENE$ (@VARIANT$; Fig. 3).",5101836,RAF1;48145,SOS1;4117,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in @GENE$, p.(@VARIANT$).",7224062,PKD1;250,PKD2;20104,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,1
"    Sequence analyses of EDA and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Functional impact of the rare variants The two missense @GENE$ variants (@VARIANT$ and (@VARIANT$) and one of the @GENE$ amino acid substitutions (p.(P179T)) were inferred to cause a moderate functional effect at least by one bioinformatic analysis and, experimentally, they were found to be associated with moderately disrupted transactivation.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the @GENE$ gene, both in heterozygous form.",6707335,CCNF;1335,ALS2;23264,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"The functional studies, via the exogenous expression approach, revealed that the @GENE$-@VARIANT$ mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of CACNA1C-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation. Conclusions Our results demonstrated that the loss-of-function CACNA1C-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in MYD88 gene and a homozygous splice-donor mutation (@VARIANT$) in CARD9 gene. (D) Western Blot of CARD9 and MYD88 proteins performed on PBMC, EBVB, and PHA derived T cell lines. (E) @GENE$ production by monocytes after LPS stimulation (mean +- SEM of n = 2). (F) Phenotypic analysis of iDC and @GENE$ differentiated in vitro.",6383679,TNFalpha;496,mDC;7529,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"(b) The changed site of SCN5A gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant DISCUSSION In our study, the proband with overlapped phenotypes of young early-onset LQTS and sinoatrial node dysfunction was first demonstrated to carry with the digenic heterozygous and pathogenic mutations of KCNH2 p.307_308del and @GENE$ @VARIANT$. @GENE$ @VARIANT$ induced a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized, which thus mainly caused LQTS.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, @VARIANT$, p.S82T, p. A85P, p.L86F, @VARIANT$, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.P79T;tmVar:p|SUB|P|79|T;HGVS:p.P79T;VariantGroup:108;CorrespondingGene:6012,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"@VARIANT$ might affect the normal splicing of exons in the PROK2 gene, and the novel variant c.306G > C (@VARIANT$) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a @GENE$ gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the @GENE$ gene were found in eight patients.",8796337,PROK2;9268,PROKR2;16368,c.223 - 4C > A;tmVar:c|SUB|C|223-4|A;HGVS:c.223-4C>A;VariantGroup:21;CorrespondingGene:60675,p. Arg102Ser;tmVar:p|SUB|R|102|S;HGVS:p.R102S;VariantGroup:20;CorrespondingGene:3730,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The effects of @GENE$-@VARIANT$ mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation. Conclusions Our results demonstrated that the loss-of-function CACNA1C-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"We report digenic variants in @GENE$ and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,CELSR1;7665,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"While tagged versions of EphA2 G355R and EphA2 T511M were effectively precipitated with Fc-fusion ephrin-A1 compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down EphA2 @VARIANT$ and T511M (Fig. 7a). Consistently, internalization of @GENE$ G355R and EphA2 T511M with pendrin induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause pendrin cytoplasmic localization. A subset of these mutations, such as H723R, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum. Low temperature incubation and salicylate treatment of cultured cells, which are thought to help with protein-folding processes, rescues the membrane localization of @VARIANT$. On the other hand, mis-localization of pendrin A372V from the plasma membrane is not restored by these treatments, suggesting these mutations may affect @GENE$ trafficking from the Golgi to the plasma membrane but not protein-folding.",7067772,EphA2;20929,pendrin;20132,G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between FLNB and @GENE$. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L @GENE$ proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"We found that @GENE$-@VARIANT$ was not associated with a severe functional impairment, whereas @GENE$-@VARIANT$, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"We report digenic variants in SCRIB and @GENE$ associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. Location analysis of missense changes showed that p.G1108E was located very close to the fourth PDZ domain (1109-1192) of SCRIB. The PDZ domains of human SCRIB are required for correct localization and physical interaction with other proteins, such as the core PCP protein VANGL2, which is required for transducing PCP signals. Herein we demonstrate that SCRIB variants combined with variants among other PCP genes might be associated with the observed NTD phenotypes in humans. However, pathogenic effect of these variants on protein function or on neural tube development need to be investigated in the future.   No reports are available in the literature on the contribution of digenic variants of CELSR1 and @GENE$ gene in the pathogenesis of NTDs.",5966321,PTK7;43672,DVL3;20928,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PTK7;43672,FAT4;14377,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes.     ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90.",3842385,WNT10A;22525,EDA;1896,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). The c.1787A>G (@VARIANT$) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: @VARIANT$ and @VARIANT$; @GENE$: p.(P179T)).,6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,UNC13B;31376,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The @GENE$ and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,SETDB1;32157,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
This indicates that neither @VARIANT$ in GJB2 nor @VARIANT$ in @GENE$ contributed to SNHL in SH60-136 and that p.R143W in @GENE$ was an incidentally detected variant in this subject.,4998745,WFS1;4380,GJB2;2975,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"No mutations in @GENE$, TPO, or @GENE$ gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) DUOX2:c.3329G>A (@VARIANT$) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,SLC5A5;37311,IYD;12352,p.R1110Q;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:22;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent @GENE$ variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: @VARIANT$ and @VARIANT$; PITX2: p.(P179T)).,6338360,PITX2;55454,FOXC2;21091,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in @GENE$, @VARIANT$ in @GENE$ and @VARIANT$ in S100A3, and one novel variant in S100A13, were identified.",6637284,ISG20L2;12814,SETDB1;32157,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.R566L, p.@VARIANT$) vector plasmids and myc-tagged WT or mutant @GENE$ (@VARIANT$, p.R50C).",7279190,FLNB;37480,TTC26;11786,A2282T;tmVar:c|SUB|A|2282|T;HGVS:c.2282A>T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.R297C;tmVar:p|SUB|R|297|C;HGVS:p.R297C;VariantGroup:8;CorrespondingGene:79989;RS#:115547267;CA#:4508260,0
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,1
"However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C @VARIANT$). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,FGFR1;69065,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, @GENE$-p.R583H and KCNH2-@VARIANT$, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas @GENE$-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"          Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the @GENE$ and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (c.791G A) resulting in substitution of a valine by methionine at position 255 (@VARIANT$) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b). This mutation was not present in 100 control alleles by restriction enzyme digestion and/or by direct nucleotide sequencing (Fig. 3c). Secondly, a single nucleotide substitution (@VARIANT$ T) resulting in substitution of a serine by phenylalanine in position 300 (p.S300F) was detected (Fig. 3d).",2900916,GGCX;639,VKORC1;11416,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,c.927C;tmVar:c|Allele|C|927;VariantGroup:3;CorrespondingGene:368;RS#:528603039,0
"2.3. Functional Consequences of the KCNQ1-@VARIANT$ and @GENE$-p.C108Y Variants To investigate the functional consequences of @GENE$-p.R583H and KCNH2-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"We report digenic variants in @GENE$ and @GENE$ associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,PTK7;43672,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (@VARIANT$), @GENE$ (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,CAPN3;52,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in @GENE$ was also identified.",7549550,RIPPLY1;138181,MYOD1;7857,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,1
"(D) The EDA mutation c.457C>T and @GENE$ mutation @VARIANT$ were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis. (E) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"To investigate the effects of one candidate variant on mutant @GENE$ function, Western blotting and coimmunofluorescence were used to assess binding capacity, and leptomycin B exposure along with immunofluorescence was used to assess nuclear localization. Results: We describe a child who presented in infancy with combined pituitary hormone deficiencies and whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father.",5505202,WDR11;41229,PROKR2;16368,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. The authors raised the possibility of a digenic myopathy, which up to date has not been proven.     Herein, we describe the clinical and pathological phenotype of three unrelated probands harboring the combined heterozygous @GENE$ and @GENE$ variants in the setting of MRV or myofibrillar pathology, providing evidence that co-occurrence of these variants are associated with late-onset myopathy.",5868303,TIA1;20692,SQSTM1;31202,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,1
The KCNQ1-@VARIANT$ variant was previously reported to be associated with LQTS; @GENE$-p.C108Y is a novel variant; and KCNH2-p.K897T and @GENE$-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels.,5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Only three variants were homozygous in three patients: (1) @GENE$: @VARIANT$ (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"(A) Patient with homozygous variants in both ANO5 and @GENE$ genes. NGS reads indicated the identification of homozygous missense pathogenic variants @VARIANT$ (p.R758C) and @VARIANT$ (R284C) in @GENE$ and SGCA genes, respectively.",6292381,SGCA;9,ANO5;100071,c.2272C>T;tmVar:c|SUB|C|2272|T;HGVS:c.2272C>T;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,c.850C>T;tmVar:c|SUB|C|850|T;HGVS:c.850C>T;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"Of note, the same variant @VARIANT$ was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the @GENE$-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)p. Gln91Arg, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant p. Val969Ile of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. CDON seems to act similarly as CCDC88C through a digenic/oligogenic model to contribute to IHH. Case P06 had a missense variant in GADL1 (p. Ser221Cys), predicted as probably damaging. @GENE$ expression is present during early brain development and is higher in olfactory bulb than that in other tissues, where is an active area for regeneration and migration of GnRH neurons.",8152424,CCDC88C;18903,GADL1;45812,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"                    By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of @GENE$ (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). This 2-year-old female showed severe autosomal recessive SNHL with a mean hearing threshold of 87.5 dB HL.   Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the p.T123N variant of GJB2. The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of USH2A (NM_007123), R5143C, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and Ankyrin 1 (ANK1) identified in SH 94-208).",4998745,GJB3;7338,USH2A;66151,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,0
"Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (p.Asn118Ser) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0
"On the contrary, the functionality of the @GENE$-@VARIANT$ channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the @GENE$-@VARIANT$ variant has pathogenic properties consistent with LQTS.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Notably, the patients carrying the @VARIANT$ and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,gap junction protein beta 2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
" Finally, a subject with the heterozygous @VARIANT$ mutation in @GENE$ (SH60-136) carried a @VARIANT$ variant in @GENE$ (WFS1) (NM_001145853) according to TES.",4998745,GJB2;2975,Wolfram syndrome 1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Patient 3 was found to harbor a previously reported @VARIANT$ variant in @GENE$, alongside a rare variant in ZFPM2 (c.A2107C, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in @GENE$ (c.G680A, @VARIANT$, rs9332964:G>A) in Patient 11, who also harbored a single codon deletion at position 372 of NR5A1 (Table 3).",5765430,NR5A1;3638,SRD5A2;37292,p.Arg84His;tmVar:p|SUB|R|84|H;HGVS:p.R84H;VariantGroup:0;CorrespondingGene:2516;RS#:543895681,p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,SPTBN4;11879,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)]. Such findings bring into question their involvement in disease expression in HH12. The SEMA7A variant [p.(Glu436Lys)] was predicted as VUS by Varsome. Sanger validation revealed the absence of this mutation in the healthy mother. The @GENE$ and @GENE$ genes were implicated in a digenic combination classified as ""dual molecular diagnosis"" by ORVAL.",8446458,SEMA7A;2678,DUSP6;55621,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (@VARIANT$), EPHA2: @VARIANT$ (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"  Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the @VARIANT$ variant of @GENE$. The pathogenic potential of the p.T123N variant is controversial. Three variants of USH2A (NM_007123), R5143C, C4870F, and @VARIANT$ with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (@GENE$) identified in SH 94-208).",4998745,GJB2;2975,ANK1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,G805A;tmVar:c|SUB|G|805|A;HGVS:c.805G>A;VariantGroup:14;CorrespondingGene:7399;RS#:587783023;CA#:270788,0
"Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of @GENE$ and C104R (@VARIANT$) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,1
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and @GENE$ p.R408C with SETX @VARIANT$ and @GENE$ @VARIANT$).,4293318,TAF15;131088,SETX;41003,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"    Sanger sequencing Sanger sequencing was performed on available samples for confirmation of @GENE$ and @GENE$ variants in family members to perform segregation analysis. Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"In AS patient IID27, the two mutations in @GENE$ and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation c.1339 + 3A>T in COL4A5, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes.",6565573,COL4A5;133559,COL4A4;20071,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"R583H was not associated with a severe functional impairment, whereas @GENE$-@VARIANT$, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and @GENE$-@VARIANT$ were previously reported to produce more severe phenotypes when combined with disease-causing alleles.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Circles, female; squares, male; gray, @GENE$/TACI @VARIANT$ mutation; blue @GENE$ @VARIANT$ mutation (as indicated).",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"At the molecular level, @GENE$ mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).      In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (@VARIANT$) was identified in @GENE$ (table 1).",6161649,N-cadherin;20424,IL17RD;9717,c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588,p.Gly226Ser;tmVar:p|SUB|G|226|S;HGVS:p.G226S;VariantGroup:5;CorrespondingGene:54756;RS#:1212415588,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"The @VARIANT$ (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"SCUBE2 forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/@GENE$ binding, thus stimulating VEGF signalling (figure 3). The @VARIANT$ (p.Cys531Tyr) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant @VARIANT$ (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in @GENE$/TGF-beta signalling (figure 3).",6161649,VEGFR2;55639,BMP;55955,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Finally, as regards the USH3 patients, biallelic mutations in @GENE$ and monoallelic mutations in VLGR1 or WHRN were found in three patients, two patients, and one patient, respectively. One USH1 and two USH2 patients were heterozygotes for mutations in two or three USH genes, suggesting a possible digenic/oligogenic inheritance of the syndrome. In the USH2 patients, however, segregation analysis did not support digenic inheritance. Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in @GENE$ (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation.",3125325,USH2A;66151,MYO7A;219,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and @GENE$ p.R408C with SETX p.I2547T and SETX @VARIANT$).,4293318,ANG;74385,TAF15;131088,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(Ser872Gly) variant in PKD1, while only one fetus inherited the p.(Arg872Gly) @GENE$ variant. The analysis of PKHD1 performed on the first fetus showed no mutations. We suggest that: 1) the PKD2 p.(Cys331Thr) variant is pathogenic, since it is de-novo in a patient with a renal cystic disease and is transmitted to both fetuses; 2) the p.(@VARIANT$) variant in PKD1 is hypomorphic, since it does not cause renal disease in the father (age 44 years), but worsens the renal phenotype when co-inherited with a PKD2 mutation; 3) the missense variant p.(@VARIANT$) in PKD2, already described as disease-causing in HGMD database (Neumann et al.,), is likely benign, since it is present in a healthy man and does not segregate with disease in the fetuses. Pedigree of Family 18287 with bilineal inheritance of @GENE$/PKD2 variants.",7224062,PKD2;20104,PKD1;250,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the NRXN1 and NRXN2 proteins lead us to hypothesize that digenic variants in @GENE$ and @GENE$ contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and TNFRSF13B/@GENE$ C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Circles, female; squares, male; gray, @GENE$/TACI @VARIANT$ mutation; blue @GENE$ T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"The genotypes of @GENE$ (NM_001257180.2: @VARIANT$, p.His596Arg) and @GENE$ (NM_002609.4: @VARIANT$, p.Arg106Pro) for available individuals are shown.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant. Currently, the genetic basis for the clinical heterogeneity of PFBC is not largely understood, and it cannot be explained only by a single variant. PFBC patients with biallelic variants in SLC20A2 have been reported. In 2012, Wang et al. reported that PFBC patients with compound heterozygous SLC20A2 mutations (c.362C>G, p.Ser121Cys and c.1802C>G, @VARIANT$) presented extremely severe brain calcification, accompanied by repetitive seizures, mental retardation, and developmental delay since infancy (Wang et al., 2012, 2015).",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.Ser601Trp;tmVar:p|SUB|S|601|W;HGVS:p.S601W;VariantGroup:0;CorrespondingGene:6575;RS#:387906652;CA#:346848,0
"Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous @GENE$ nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of @GENE$ (c.1823-1G>C) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX2;9689,DUOX1;68136,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the TNFRSF13B/TACI C104R mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant TCF3 T168fsX191 gene. Exons coding E2A functional domains, activation domain 1 and 2 (AD1, @GENE$) and helix-loop-helix (HLH) domains are shown.",5671988,TACI;49320,AD2;30951,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Immunocomplex of myc-pendrin @VARIANT$, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated @GENE$ triggered by @GENE$ stimulation.",7067772,pendrin;20132,ephrin-B2;3019,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Sequence alterations were detected in the COL6A3 (@VARIANT$), @GENE$ (rs143445685), @GENE$ (rs138172448), and DES (@VARIANT$) genes.",6180278,RYR1;68069,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Three SNPs in SETX (@VARIANT$, rs543573, and rs2296871) were in perfect linkage disequilibrium and were considered to be one signal represented by rs2296871. We included only ALS subjects of European ancestry and compared to controls of European ancestry from ESP6500 and the 1000 Genomes Project. SPLINTER-predicted allele frequencies were used for common variants that were not confirmed by genotyping in ALS subjects. Using a Bonferonni-corrected significance level of 8.2x10-4, 3 variants were significantly more common in our ALS discovery cohort (rs3739927 and rs882709 in @GENE$, and @VARIANT$ in @GENE$).",4293318,SETX;41003,EWSR1;136069,rs1183768;tmVar:rs1183768;VariantGroup:64;CorrespondingGene:23064;RS#:1183768,rs41311143;tmVar:rs41311143;VariantGroup:21;CorrespondingGene:2130;RS#:41311143,0
"The @VARIANT$ (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of @GENE$. Direct sequence analysis showing the @VARIANT$ (N166S) mutation (d) and WT allele (e) of @GENE$. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3.,2737700,GJB2;2975,GJB3;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,497A>G;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"KCNH2 p.307_308del and SCN5A @VARIANT$ of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A p.R1865H. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of @GENE$ p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus lead to a reduction of structural stability. However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d).",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
Future studies will focus on determining how double homozygous mutations in SEC23A (@VARIANT$) and @GENE$ (@VARIANT$) result in increased intracellular pro-@GENE$ levels and increased pro-COLA1 secretion.,4853519,MAN1B1;5230,COL1A1;73874,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of @GENE$ and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB6;4936,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (@VARIANT$) and @GENE$: c.1229C>A (p.410T>M), @GENE$: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"His cells produced higher levels of IgG and IgM than his mother (II.2, who bears both the TNFRSF13B/TACI C104R and @GENE$ @VARIANT$ mutations).    The combination of TCF3 T168fsX191and @GENE$/TACI @VARIANT$ mutations in the proband resulted in a greater net effect that the sum of each individual mutation would predict than the sum of deficits observed for each mutation alone (that is, Ig levelIII.2-(IgIII.2-IgIII.1)+(IgIII.2-IgII.3)).",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ TTC26 proteins pulled down the Flag-tagged mutant p.A2282T and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type @GENE$ and wild-type @GENE$, which did not exist between @VARIANT$ FLNB and p.Y437F OFD1 (figure 3D).",7279190,OFD1;2677,FLNB;37480,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"His cells produced higher levels of IgG and IgM than his mother (II.2, who bears both the TNFRSF13B/TACI C104R and TCF3 @VARIANT$ mutations).    The combination of @GENE$ T168fsX191and TNFRSF13B/@GENE$ @VARIANT$ mutations in the proband resulted in a greater net effect that the sum of each individual mutation would predict than the sum of deficits observed for each mutation alone (that is, Ig levelIII.2-(IgIII.2-IgIII.1)+(IgIII.2-IgII.3)).",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Thus, the @VARIANT$ SEC23A mutation does not modulate levels of @GENE$. However, the @VARIANT$ @GENE$ mutation results in decreased levels of MAN1B1 in homozygous patients as well as in unaffected carriers.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 @VARIANT$ and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A).",5887939,PRICKLE4;22752,DVL3;20928,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,0
"Interestingly, four of these @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"The mother and son reported by Beijers et al. were heterozygous for @GENE$ G31D and @GENE$ @VARIANT$, but the @VARIANT$ substitution has subsequently been identified in 7/4300 European exomes (Exome variant server, NHLBI GO Exome Sequencing Project http://evs.gs.washington.edu/EVS/).",4090307,HNF1A;459,HNF4A;395,H214Y;tmVar:p|SUB|H|214|Y;HGVS:p.H214Y;VariantGroup:5;CorrespondingGene:3172,G31D;tmVar:p|SUB|G|31|D;HGVS:p.G31D;VariantGroup:4;CorrespondingGene:6927;RS#:137853247;CA#:124487,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of @GENE$) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,DVL3;20928,SCRIB;44228,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,0
"The presence of concomitant mutations, such as the @GENE$ T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/@GENE$ @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,1
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in @GENE$. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 @VARIANT$ with SETX p.I2547T and SETX p.T14I).",4293318,TARDBP;7221,ATXN2;2234,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Despite being predicted as benign by Varsome, this variant [@VARIANT$] was involved in the second most important pathogenic combinations (15%; 13 genes) in HH1, after the PROKR2 gene variant [p.(Pro290Ser)]. On the other hand, when the @GENE$ variant was at a heterozygous state, prediction by ORVAL yielded only two pathogenic digenic combinations with PROKR2 and @GENE$ variants in HH1F and HH1P cases (Figure 4). The variant pair CCDC141 (c.2803C > T)-PROKR2 (c.868C > T) was classified by ORVAL as true digenic. The contribution of the three missense variants in IL17RD and PCSK1 genes, which were homozygous in the index case and heterozygous in the asymptomatic cases (Table 2), to the total number of pathogenic digenic combinations did not differ among the three family members (Figure 4). This indicates their minor contribution to disease expression in HH1. The splice site variant (@VARIANT$) in the SMCDH1 gene (NM_015295), only present in the index case (Table 2), was not involved in any disease-causing digenic combination.",8446458,CCDC141;52149,DUSP6;55621,p.(Arg935Trp);tmVar:p|SUB|R|935|W;HGVS:p.R935W;VariantGroup:4;CorrespondingGene:285025;RS#:17362588,c.5476 + 10A > G;tmVar:c|SUB|A|5476+10|G;HGVS:c.5476+10A>G;VariantGroup:1;CorrespondingGene:23347;RS#:3213926,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, @GENE$ p.R769W, DVL3 p.R148Q, PTK7 @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
" Finally, a subject with the heterozygous p.R143W mutation in @GENE$ (SH60-136) carried a p.D771N variant in @GENE$ (WFS1) (NM_001145853) according to TES. However, neither p.R143W in GJB2 nor p.D771N in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3). As a result, DFNB1 was excluded for SH60-136. Pedigree and audiograms of SH60 and segregation of variations of GJB2 and WFS1 in this family: two subjects with SNHL, SH60-138 and SH60-142, showed a discrepancy in the GJB2 genotype. Two unaffected subjects, SH60-137 and SH60-139, also carried @VARIANT$ in WFS1. This indicates that neither @VARIANT$ in GJB2 nor p.D771N in WFS1 contributed to SNHL in SH60-136 and that p.R143W in GJB2 was an incidentally detected variant in this subject.",4998745,GJB2;2975,Wolfram syndrome 1;4380,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, @VARIANT$, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,SPTBN4;11879,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, @VARIANT$), @GENE$ p.307_308del (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS.",8739608,KCNH2;201,SCN5A;22738,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: @VARIANT$ (p.R559W) and PKHD1: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.1675C > T;tmVar:c|SUB|C|1675|T;HGVS:c.1675C>T;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488,1
"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,CDH23;11142,MYO7A;219,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Eight pathogenic or presumably pathogenic mutations in @GENE$ were found in six patients, specifically, a previously reported mutation that affects splicing (c.6050-9G>A), a novel nucleotide deletion (c.6404_6405delAG; p.E2135fsX31), and six missense mutations, four of which (p.R1189W, p.R1379P, p.D2639G, and @VARIANT$) had not been previously reported. They affect amino acid residues located in the 11th, 13th and 25th cadherin repeat and the extracellular region adjacent to the transmembrane domain (3065-3085), respectively (Tables 2, 3 Figure 1). Intriguingly, the p.R1060W mutation, which affects a residue in the 10th cadherin repeat that belongs to a canonical motif (DRE) predicted to bind Ca2+ , has previously been reported in an isolated form of deafness, DFNB12 (cited in Astuto et al.). Two pathogenic or presumably pathogenic mutations in @GENE$, specifically, a nonsense mutation (@VARIANT$) and a novel missense mutation (p.R1273S), were found in two patients.",3125325,CDH23;11142,PCDH15;23401,p.R3043W;tmVar:p|SUB|R|3043|W;HGVS:p.R3043W;VariantGroup:141;CorrespondingGene:64072;RS#:375907609;CA#:5546888,p.R991X;tmVar:p|SUB|R|991|X;HGVS:p.R991X;VariantGroup:51;CorrespondingGene:65217;RS#:754391973;CA#:351436,0
"RNA secondary structure of KCNH2 @VARIANT$ showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Nav1.5 protein property, SCN5A @VARIANT$ slightly increased the molecular weight and aliphatic index but reduced the instability index.   Conclusions The digenic heterozygous @GENE$ and @GENE$ mutations were associated with young early-onset long QT syndrome and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"        Molecular Data All three probands carry two heterozygous variants: @GENE$, c.1175C>T (@VARIANT$), and @GENE$, c.1070A>G (@VARIANT$).",5868303,SQSTM1;31202,TIA1;20692,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"His cells produced higher levels of IgG and IgM than his mother (II.2, who bears both the TNFRSF13B/TACI C104R and @GENE$ @VARIANT$ mutations).    The combination of TCF3 T168fsX191and TNFRSF13B/@GENE$ @VARIANT$ mutations in the proband resulted in a greater net effect that the sum of each individual mutation would predict than the sum of deficits observed for each mutation alone (that is, Ig levelIII.2-(IgIII.2-IgIII.1)+(IgIII.2-IgII.3)).",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and @GENE$ F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA.",7067772,pendrin;20132,EPHA2;20929,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal @GENE$ domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary CYP1B1-binding site.",5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in @GENE$, USH1G and @GENE$ were not found in 666 control alleles.",3125325,MYO7A;219,USH2A;66151,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"The other two @GENE$ variants, @VARIANT$ (p.Ser817Cys) and c.4333A>G (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the @GENE$ mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance.",8621929,LRP6;1747,WNT10A;22525,c.2450C>G;tmVar:c|SUB|C|2450|G;HGVS:c.2450C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1;68136,DUOX1 and -2;53905;50506,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"Of the 28 rare variants, eight were truncating or null variants, including four nonsense (@GENE$ gene: p.K530X and p.G1521X; @GENE$ gene: p.Y246X and p.Y138X), three splicing (DUOX2 gene: IVS17+1G>T, IVS28+1G>T; TG: @VARIANT$), and one frameshift mutation (TG gene: p.C687LfsX34). All variants were located at highly conserved regions or critical functional domains and were predicted to be disease causing by computational software (Table 3 and Table S4, Figure 2 and Figure S1). These variants were classified as pathogenic, with the exception of one nonsense variant, DUOX2 @VARIANT$ (p.G1521X).",6098846,DUOX2;9689,DUOXA2;57037,IVS10-1G>A;tmVar:c|SUB|G|IVS10-1|A;HGVS:c.IVS10-1G>A;VariantGroup:43;CorrespondingGene:5172,c.4561G>T;tmVar:c|SUB|G|4561|T;HGVS:c.4561G>T;VariantGroup:15;CorrespondingGene:50506;RS#:765781255;CA#:7537465,0
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis.",3842385,EDA;1896,WNT10A;22525,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 @VARIANT$, @GENE$ p.P642R, SCRIB @VARIANT$, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"These phenotypes were specific, since coinjection of nonmutant human @GENE$ or @GENE$ mRNA rescued all phenotypes (Fig. 3, and Fig. S4 in the Supplementary Appendix). RNF216 mRNA encoding @VARIANT$ and OTUD4 mRNA encoding @VARIANT$ were less effective in rescuing the phenotypes induced by double-MO injection (Fig. 3, and Fig. S4 in the Supplementary Appendix), suggesting not only that these mutant alleles encode functionally deficient proteins but also that epistatic interactions between these mutations contribute to the disease phenotype in the index pedigree.",3738065,RNF216;19442,OTUD4;35370,R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853,G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858,0
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of @GENE$ (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Representative western blot and bar graph showing expression levels of SEC23A (A) and MAN1B1 (B) proteins in wild-type (Wt); @GENE$ M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts. The error bars represent standard error of the mean (SEM). Differences in protein levels were detected by one-way ANOVA (analysis of variance), followed by Tukey's multiple comparison test. @GENE$ was used as an internal control. ***, P < 0.001.",4853519,SEC23A;4642,GAPDH;107053,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Pedigree and sequence chromatograms of the patient with the @VARIANT$ in MYO7A and c.158-1G>A in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in @GENE$. Another variation, @VARIANT$ in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0
"The p.Ile312Met (@VARIANT$) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
   Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the @GENE$ gene and in exon 4 (c.872 C > G; @VARIANT$) of the @GENE$ gene were identified.,8306687,GCK;55440,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Most had C9orf72 repeat expansion combined with another mutation (e.g. VCP @VARIANT$ or @GENE$ A321V; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in @GENE$ and A90V in TARDBP.",5445258,TARDBP;7221,ALS2;23264,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"We suggest that: 1) the PKD2 p.(@VARIANT$) variant is pathogenic, since it is de-novo in a patient with a renal cystic disease and is transmitted to both fetuses; 2) the p.(@VARIANT$) variant in PKD1 is hypomorphic, since it does not cause renal disease in the father (age 44 years), but worsens the renal phenotype when co-inherited with a PKD2 mutation; 3) the missense variant p.(Arg872Gly) in PKD2, already described as disease-causing in HGMD database (Neumann et al.,), is likely benign, since it is present in a healthy man and does not segregate with disease in the fetuses. Pedigree of Family 18287 with bilineal inheritance of @GENE$/@GENE$ variants.",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,1
"The proband described by Forlani et al. was heterozygous for @GENE$ E508K and HNF4A @VARIANT$. Both mutations are novel and whilst a different mutation, R80W, has been reported in @GENE$, further evidence to support the pathogenicity of @VARIANT$ is lacking.",4090307,HNF1A;459,HNF4A;395,R80Q;tmVar:p|SUB|R|80|Q;HGVS:p.R80Q;VariantGroup:2;CorrespondingGene:3172,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"@GENE$ p.307_308del and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A p.R1865H. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus lead to a reduction of structural stability. However, SCN5A p.R1865H showed no significant influence on the RNA structure (Figure 4c,d). The MFE of @GENE$ @VARIANT$ mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,alsin;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"In AS patient IID27, the two mutations in @GENE$ and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation c.1339 + 3A>T in COL4A5, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A4;20071,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"For example, two variants in proband P15, @VARIANT$ in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while @GENE$ p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,DMXL2;41022,CCDC88C;18903,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the @GENE$ protein (c.229C>T; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in @GENE$. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,1
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; @VARIANT$, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,g.146466A>G;tmVar:g|SUB|A|146466|G;HGVS:g.146466A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"In this family, the patient (II: 1) with digenic heterozygous mutations of @GENE$ @VARIANT$ and @GENE$ @VARIANT$ presented the earliest phenotype of LQTS, and she suffered from syncope, torsades de pointes, and ventricular fibrillation more frequently at rest, whereas the members (I:1 and II:2) without KCNH2 p.307_308del showed normal QT intervals and cardiac function.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1
"The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the ABCC6 gene (@VARIANT$) and the @GENE$ gene (@VARIANT$) yet did not display any cutaneous findings are not clear. Specifically, while both GGCX mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the p.S300F mutation was more pronounced than that of p.V255M. In this context, it should be noted that the substrate employed in the carboxylase assay is a pentapeptide, Phe-Leu-Glu-Glu-Leu, and it is possible that the activity measurements if done on full-length @GENE$ as substrate would show differential activity with these two mutant enzymes.",2900916,GGCX;639,MGP;693,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0
"Phenotype penetrance CACNA1C-@VARIANT$ +/-SCN5A-@VARIANT$ +/- @GENE$-Q1916R +/-@GENE$-R1193Q -/- CACNA1C-Q1916R -/-SCN5A-R1193Q -/- Male 100% (4/4 cases) 100% (1/1 case) 0 (0/1 cases) II-4, III-1, III-5, IV-3 III-7 III-3 Female 0 (0/4 cases) 100% (1/1 case) 0 (0/4case) II-3, II-6, III-4, IV-1 IV-4 II-5, III-2, III-6, III-8  Dysfunctional electrophysiology and drug intervention in mutated CaV1.2alpha1C To determine the molecular consequences of the CACNA1C-Q1916R mutation, we transfected CACNA1C with the other 2 subunits (CACNB2b and CACNA2D1) forming the LTCC into HEK293T cells and performed whole cell patch-clamp experiments.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: @VARIANT$ (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"A single @GENE$ mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated. The authors raised the possibility of a digenic myopathy, which up to date has not been proven.     Herein, we describe the clinical and pathological phenotype of three unrelated probands harboring the combined heterozygous @GENE$ and SQSTM1 variants in the setting of MRV or myofibrillar pathology, providing evidence that co-occurrence of these variants are associated with late-onset myopathy.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"A novel missense mutation was found in @GENE$ (c.398G>A, @VARIANT$). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, p.H678R and @VARIANT$, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001).",6098846,DUOXA2;57037,DUOX2;9689,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,p.S1067L;tmVar:p|SUB|S|1067|L;HGVS:p.S1067L;VariantGroup:4;CorrespondingGene:50506;RS#:269868;CA#:7537960,0
"However, one patient had a @GENE$ mutation on one of the alleles (@VARIANT$), but no mutation on the other allele. Other monoallelic mutations of GNRHR have been reported in patients with CHH and have challenged the traditional view of GNRHR as a recessive gene. It has been suggested that such patients with monoallelic mutations may have additional mutations in other genes that act synergistically to produce the phenotype. To explore this possibility, we screened this patient for mutations in other commonly implicated genes in CHH and identified an additional heterozygous missense mutation (@VARIANT$) in the PROKR2 gene. Interestingly, the same heterozygous @GENE$ mutation has been identified in a Brazilian patient with Kallmann syndrome and has been shown to exert a dominant-negative effect under certain in vitro conditions.",5527354,GNRHR;350,PROKR2;16368,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L @GENE$ variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients.",6707335,NEFH;40755,GRN;1577,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/@GENE$ @VARIANT$ mutations. Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and @GENE$ (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: @VARIANT$, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as @GENE$ induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients.",7689793,EBNA1BP2;4969,Calpain-9;38208,c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and @GENE$. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ TTC26 proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ FLNB proteins, respectively (figure 2D, E).",7279190,FLNB;37480,TTC26;11786,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,0
"   The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,1
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant c.10147G>A).",5887939,FZD;8321;8323,FAT4;14377,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (@VARIANT$; p.L16V) and @GENE$ (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in MYO7A and USH1G, and, all the more, the mutations in the three genes (Figure 2). Therefore, a combination of monoallelic mutations in three USH genes may be responsible for the disease in this patient. Segregation of the mutations in MYO7A, @GENE$ and USH2A in family U3.",3125325,USH2A;66151,USH1G;56113,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"Sequence alterations were detected in the COL6A3 (rs144651558), RYR1 (@VARIANT$), @GENE$ (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,CAPN3;52,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,ENG;92,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that @GENE$ could control both @GENE$ recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"The hot spot variant @VARIANT$ (p. Trp178Ser) was found in six patients and located in the transmembrane domain of the protein, which could significantly reduce the release of ionized calcium and the signal activity.                             The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the @GENE$/FGFR1 signalling pathway. @GENE$ signalling is essential for the migration, secretion, or survival of hypothalamic GnRH neurons and is widely expressed in the nervous and skeletal systems. The FGFR1 gene is inherited through an autosomal dominant mode. Loss of function can lead to both nIHH and KS, and more than 200 variants of the FGFR1 gene have been found in patients with IHH. The FGFR1 gene had the highest variant frequency, approximately 44% in our study, which was higher than that (10%) in the Caucasian population. Its variant can cause cleft lip and palate, short stature, and bone dysplasia. Among the 11 FGFR1 variants reported in our study, c.761G > A (p. Arg254Gln), c.232C > T (p. Arg78Cys), and c.2008G > A (@VARIANT$) were found to be pathogenic variants.",8796337,FGF;8822;8822,FGFR1;69065,c.533G > C;tmVar:c|SUB|G|533|C;HGVS:c.533G>C;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917,p. Glu670Lys;tmVar:p|SUB|E|670|K;HGVS:p.E670K;VariantGroup:1;CorrespondingGene:2260;RS#:397515446;CA#:143804,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 @VARIANT$ and GFP-@GENE$ E229K to immunoprecipitate HA-@GENE$ E103D and HA-TEK @VARIANT$, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Circles: females; squares: males; white symbols: not included in the study; white symbols with genotype: unaffected; black symbols: pulmonary fibrosis affected; +: wild-type ""C"" allele of S100A3/wild-type sequence of @GENE$; -: mutant ""T"" allele of @GENE$ (@VARIANT$)/4 bp deletion of S100A13 (@VARIANT$).",6637284,S100A13;7523,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$).",5887939,CELSR1;7665,PRICKLE4;22752,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6.",6610752,LQT2;201,KCNE2;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Among the 8 novel variants, 4 were classified as P (p.C176R and @VARIANT$ in @GENE$, @VARIANT$ in DUOX2) or LP (p.D137E in @GENE$), the other were classified as VUS.",7248516,TSHR;315,DUOX2;9689,p.K618*;tmVar:p|SUB|K|618|*;HGVS:p.K618*;VariantGroup:4;CorrespondingGene:7253,p.T803fs;tmVar:p|FS|T|803||;HGVS:p.T803fsX;VariantGroup:61;CorrespondingGene:50506,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROK2;9268,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"In patient AVM359, one heterozygous VUS (@VARIANT$ [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in @GENE$ were identified (online supplementary table S2).",6161649,ENG;92,SCUBE2;36383,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, @VARIANT$, p. A85P, @VARIANT$, p.F112S, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.S82T;tmVar:p|SUB|S|82|T;HGVS:p.S82T;VariantGroup:111;CorrespondingGene:6012,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,0
"Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,FGFR1;69065,DCC;21081,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
   Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the @GENE$ gene and in exon 4 (@VARIANT$; p.Pro291Arg) of the @GENE$ gene were identified.,8306687,GCK;55440,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CACNA1A;56383,TRPV4;11003,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,0
The @GENE$-@VARIANT$ variant was previously reported to be associated with LQTS; KCNH2-p.C108Y is a novel variant; and KCNH2-p.K897T and @GENE$-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels.,5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Both the @GENE$ and @GENE$/E2A networks share nodes of intracellular signal integration (Figure 2), mutations of which appear to have synergistically (epistatically) impaired B-cell function in the proband (II.2). In her case, the two mutations, which lie in tandem along the Ig isotype switching and secretion pathway (Figure 2), lead to severely impaired B-cell differentiation and production of IgG in vitro (Figures 3 and 4) and in severe clinical disease (Table 1, summarised in Figure 6). The proband, carrying both mutations shows the largest defect in vitro after isolated naive B cells are specifically engaged via CD40, APRIL or Toll-like receptorss and is much more severely affected than her parents, her son and her siblings. Her in vitro IgG production is substantially lower than that of her TNFRSF13B/TACI @VARIANT$ heterozygous brother (II.3) and her TCF3 @VARIANT$ heterozygous son (III.1), who individually bear each mutation.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene @GENE$ were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PTK7;43672,FZD1;20750,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (c.1514G>A, @VARIANT$). A novel missense mutation was found in @GENE$ (c.398G>A, @VARIANT$).",6098846,TG;2430,DUOXA2;57037,p.G505D;tmVar:p|SUB|G|505|D;HGVS:p.G505D;VariantGroup:10;CorrespondingGene:7173;RS#:867829370,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, @VARIANT$ in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, @GENE$ and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for CDH23 , 11%-15% for PCDH15 , and for USH2A in USH2 patients, whereas the implication of VLGR1 and WHRN in the latter was minor.",3125325,USH2A;66151,CDH23;11142,c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (p.Asn118Ser) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Among the six variants (Table 2), two are missense variants in the @GENE$ (RBM43) gene (@VARIANT$) and the dermatopontin (@GENE$) gene (@VARIANT$).",5611365,RNA Binding Motif Protein 43;12715,DPT;1458,p.V34L;tmVar:p|SUB|V|34|L;HGVS:p.V34L;VariantGroup:31;CorrespondingGene:375287;RS#:147060862;CA#:1902988,p.Y149C;tmVar:p|SUB|Y|149|C;HGVS:p.Y149C;VariantGroup:15;CorrespondingGene:1805;RS#:777651623;CA#:1231264,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and c.850C>T (@VARIANT$) in ANO5 and SGCA genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in ANO5 gene and one pathogenic variant in COL6A2 gene indicating multiple gene contributions for an unusual presentation. His mother, a 40-year-old female with one pathogenic variant each in @GENE$ and @GENE$ shows unspecified myopathy with elevated creatine phosphokinase (CPK).",6292381,ANO5;100071,COL6A2;1392,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,R284C;tmVar:p|SUB|R|284|C;HGVS:p.R284C;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of @GENE$).,3888818,KAL1;55445,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both FOXC1 and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with @GENE$ that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely @VARIANT$, p.P79T, p.S82T, p. A85P, @VARIANT$, p.F112S, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,PITX2;55454,FOXC1;20373,p.Q70Hfs*8;tmVar:p|FS|Q|70|H|8;HGVS:p.Q70HfsX8;VariantGroup:8;CorrespondingGene:6012,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: @VARIANT$, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,TOR2A;25260,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"The functional consequence of @GENE$-p.C108Y was investigated by analyzing the ionic currents from cells expressing KCNH2-WT or KCNH2-@VARIANT$ and from cells co-expressing both alleles. 2.3.1. Functional Effects of KCNQ1-p.R583H The expression of KCNQ1-p.R583H in CHO-K1 cells evoked robust outward currents, and no significant differences in activating and tail current densities were identified between cells expressing a @GENE$-p.R583H channel and cells expressing a KCNQ1-WT channel. However, there was a statistically significant positive shift in the voltage-dependence of activation (V1/2: KCNQ1-WT, -21.1 +- 0.86 mV, n = 13; KCNQ1-@VARIANT$, -16.7 +- 1.22 mV, n = 11, p < 0.05) without a significant alteration in the slope factor (k: KCNQ1-WT, 3.5 +- 0.7 mV, n = 13; KCNQ1-p.R583H, 4.6 +- 1.2 mV, n = 11, p > 0.05).",5578023,KCNH2;201,KCNQ1;100761481,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, @VARIANT$; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"(A) Patient with homozygous variants in both @GENE$ and SGCA genes. NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and c.850C>T (@VARIANT$) in ANO5 and @GENE$ genes, respectively.",6292381,ANO5;100071,SGCA;9,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,R284C;tmVar:p|SUB|R|284|C;HGVS:p.R284C;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, @VARIANT$ and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the @VARIANT$ substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,c.475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/@GENE$-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,DCC;21081,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,1
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, @VARIANT$ (p.Pro392Leu).",5868303,TIA1;20692,SQSTM1;31202,c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,c.1175C > T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,1
"(E) The @GENE$ mutation c.466C>T and @GENE$ mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in EDA and c.511C>T in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 @VARIANT$ and GFP-@GENE$ E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK @VARIANT$ (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-@GENE$ proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,CAPN11;21392,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; @VARIANT$) c.1226A>G; p.N409S and @GENE$ (MIM 600509; NM_000352.4; @VARIANT$) c.3989-9G>A mutations.,5505202,GBA;68040,ABCC8;68048,rs7673715;tmVar:rs7673715;VariantGroup:2;RS#:7673715,rs151344623;tmVar:rs151344623;VariantGroup:4;CorrespondingGene:6833;RS#:151344623,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"A novel variant SCRIB @VARIANT$ (p.K618R) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and @GENE$ p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,DVL3;20928,SCRIB;44228,c.1853A > G;tmVar:c|SUB|A|1853|G;HGVS:c.1853A>G;VariantGroup:2;CorrespondingGene:5754;RS#:139041676;CA#:3816321,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and @GENE$/TACI @VARIANT$ mutations.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,1
"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (@VARIANT$; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,USH1G;56113,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"The study revealed @GENE$ gene mutations in a majority of our cohort (33%), in accordance with the percentages already reported in the literature. Interestingly, we found just one patient with variants in BBS1, the most frequently detected gene in BBS patients. We identified a novel variant in BBS1 patient #10 @VARIANT$ (p.(Arg429Profs*72)) defined as pathogenic that segregates with phenotype together with c.46A > T (p.(Ser16Cys), defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, was identified in patient #3. @GENE$, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS10;49781,BBS1;11641,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, @VARIANT$, was identified in patient #3. @GENE$, BBS2 and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS1;11641,BBS7;12395,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"This is in line with the data from previous studies; according to which, @GENE$ is a causative gene of ALS-FTD. The NEK1 @VARIANT$ variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    @GENE$ variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (L106V and R572W). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form.",6707335,TBK1;22742,CCNF;1335,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Moreover, the overt LQTS phenotype in our family could be caused by the co-expression, in cardiac cells, of @GENE$-@VARIANT$ and @GENE$-@VARIANT$. The condition of digenic heterozygosity has been associated with a more severe phenotype, a higher risk of life-threatening events, and a reduced efficacy of beta blocking therapy.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,1
"In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
"This genetic synergism is also supported by the potential digenic inheritance of LRP6 and @GENE$ mutations in Family 4. The proband, who had @GENE$ p.(Asn1075Ser), p.(@VARIANT$), and WNT10A p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,WNT10A;22525,LRP6;1747,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (@VARIANT$) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"The latter individuals were also carriers of the ABCC6 nonsense mutation @VARIANT$. It should be noted that the mother and her twin sister were heterozygous for one of the @GENE$ missense mutation @VARIANT$ and one @GENE$ nonsense mutation p.R1141X, suggesting digenic inheritance of their cutaneous findings.",2900916,GGCX;639,ABCC6;55559,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,DNAH17;72102,MRPL15;32210,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Only three variants were homozygous in three patients: (1) DUOX2: @VARIANT$ (p.M927V) in one patient, (2) @GENE$:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"We identified a novel variant in BBS1 patient #10 c.1285dup (p.(Arg429Profs*72)) defined as pathogenic that segregates with phenotype together with @VARIANT$ (p.(Ser16Cys), defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (@VARIANT$; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, was identified in patient #3. @GENE$, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS7;12395,BBS1;11641,c.46A > T;tmVar:c|SUB|A|46|T;HGVS:c.46A>T;VariantGroup:5;CorrespondingGene:582;RS#:772917364,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,0
"Thirteen (72.2%) of 18 patients were identified eleven variants in eight known causative genes, namely AXL receptor tyrosine kinase (AXL), coiled-coil domain containing 141 (@GENE$), chromodomain helicase DNA binding protein 7 (CHD7), Dmx like 2 (DMXL2), fibroblast growth factor receptor 1 (FGFR1), patatin like phospholipase domain containing 6 (PNPLA6), @GENE$ (POLR3A) and prokineticin receptor 2 (PROKR2), see (Table 1 and 2). The PROKR2 missense variant p. Trp178Ser was recurrently observed in three patients, and was statistically enriched in our IHH cohort compared to the population (3/18 in the IHH cases vs 56/9976 in the gnomAD East Asians, P = 0.00015, one-tailed Fisher's exact test). Furthermore, another PROKR2 missense variant @VARIANT$ was identified in case P15. All of the remaining deleterious variants in the other seven known IHH genes were novel and unreported. Notably, the novel LoF variant FGFR1 @VARIANT$ in case P05 is de novo and evaluated as pathogenic.",8152424,CCDC141;52149,RNA polymerase III subunit A;5124,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 @VARIANT$, DVL3 p.R148Q, PTK7 @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys).",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
@GENE$ @VARIANT$ and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and KCNH2 mutations. @GENE$ @VARIANT$ and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing.,8739608,SCN5A;22738,KCNH2;201,p.R1865;tmVar:p|Allele|R|1865;VariantGroup:1;CorrespondingGene:6331;RS#:370694515,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in @GENE$ (@VARIANT$) and @GENE$ (@VARIANT$), both sarcomeric genes.",6359299,MYH7;68044,TNNT2;68050,Asp955Asn;tmVar:p|SUB|D|955|N;HGVS:p.D955N;VariantGroup:2;CorrespondingGene:4625;RS#:886039204;CA#:10587773,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,1
"Genotype + and - indicate in the figure wild type and mutated, respectively. (B) Percentage of CD3+CD4+@GENE$+ cells after PMA stimulation (mean +- SEM of n = 2). (C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in MYD88 gene and a homozygous splice-donor mutation (@VARIANT$) in @GENE$ gene.",6383679,IL17;1651,CARD9;14150,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, DUOX2, DUOXA2 and TPO).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a @GENE$ mutation in association with mutation(s) in different genes. A total of 2 novel variants, p.S309P and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and @VARIANT$ and @VARIANT$ were novel.",7248516,SLC26A4;20132,TPO;461,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,p.K618;tmVar:p|Allele|K|618;VariantGroup:4;CorrespondingGene:7253,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and TAF15 p.R408C with @GENE$ p.I2547T and SETX p.T14I).",4293318,ANG;74385,SETX;41003,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by @GENE$. 20  The identified @GENE$ (NM_001202543: c.1438A > G, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS.",7689793,OGG1;1909,CUX1;22551,c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"As shown in Supplementary Fig. 3a, the mutant HA-@GENE$ proteins @VARIANT$ and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-@GENE$ @VARIANT$ and R368H showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Since OFD1 localises to the base of the cilium, we assumed that @GENE$ may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ FLNB and @VARIANT$ @GENE$ (figure 3D).",7279190,FLNB;37480,OFD1;2677,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"He had no mutations in CHD7, @GENE$, FGFR1, PROK2, PROKR2, TAC3, @GENE$, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;@VARIANT$ from NP_056352). Since Thr478 was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease.",3888818,FGF8;7715,KAL1;55445,p.Thr478Ala;tmVar:p|SUB|T|478|A;HGVS:p.T478A;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0
"GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). The WT and mutant @GENE$ proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins @VARIANT$ and I148T exhibited diminished interaction with wild-type GFP-CYP1B1.",5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: @VARIANT$ (p.R559W) and PKHD1: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.1675C > T;tmVar:c|SUB|C|1675|T;HGVS:c.1675C>T;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488,1
"(F) The mutations @VARIANT$ in @GENE$ and @VARIANT$ in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the @GENE$ missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro.",4470809,OPTN;11085,TBK1;22742,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/@GENE$ C104R mutations are shown.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Interestingly, case C (NM_013254.3:c.2086G>A ; p.Glu696Lys) and case E (NM_013254.3:c.1201A>G; p.Lys401Glu) showed greatly reduced TBK1 protein levels, comparable to case B, while in case D (NM_013254.3:@VARIANT$; p.Leu306Ile) TBK1 levels were normal (Figure 3).   @GENE$ and TBK1 double mutations are associated with FTLD pathology without clinical motor neuron disease Clinical and pathological features of cases A-E with possible pathogenic mutations in TBK1/OPTN are summarized in Table 2. Detailed case reports of the TBK1 and OPTN double mutants are included below:   Case B (OPTN p.Gly538Glufs27; @GENE$ @VARIANT$) was a Caucasian male who started having significant cognitive difficulties at the age of 68.",4470809,OPTN;11085,TBK1;22742,c.916C>A;tmVar:c|SUB|C|916|A;HGVS:c.916C>A;VariantGroup:2;CorrespondingGene:29110;RS#:201970436;CA#:6668923,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT6;71688,LQT2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), @GENE$: c.1063G>A (p.G355R) and @GENE$: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
The p.Ala349Thr (@VARIANT$) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (@VARIANT$) mutation in exon 3 of @GENE$ were detected.,3842385,EDA;1896,WNT10A;22525,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"   The substitutions of Leu117 to Phe (L117F), @VARIANT$ (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic @GENE$ and SLC26A4 mutations.",7067772,pendrin;20132,EPHA2;20929,Ser166 to Asn;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Specifically, heterozygous missense mutations in neighboring residues A435 (c.1303G>A;@VARIANT$; rs318240760) and R448 (c.1343G>A;p.R448Q; rs144440500) have been identified in each of two individuals with idiopathic hypogonadotropic hypogonadism and normosmia. In addition, in a different individual, the @GENE$ p.A435T mutation was identified in association with a mutation in a second gene, @GENE$ (c.275T>C;@VARIANT$; MIM 138850; NM_000406.2), implicating digenic inheritance of this disorder as well.",5505202,WDR11;41229,GNRHR;350,p.A435T;tmVar:p|SUB|A|435|T;HGVS:p.A435T;VariantGroup:0;CorrespondingGene:55717;RS#:318240760;CA#:130157,p.L92P;tmVar:p|SUB|L|92|P;HGVS:p.L92P;VariantGroup:8;CorrespondingGene:2629;RS#:1141815,0
"The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,SETDB1;32157,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,VPS13C;41188,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Mice lacking @GENE$ develop cardiomyopathy and have an increased frequency of sudden death upon stress; electron microscopy of these mice revealed malformed blood vessels and micro-circulation abnormalities. Moreover, patients carrying a LAMA4 Pro943Leu mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and @GENE$ (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYBPC3;215,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in @GENE$ (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with @GENE$ mutation.",7877624,TYRO3;4585,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Notably, the patients carrying the @VARIANT$ and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"A, The pedigree shows the coinheritance of the monoallelic variants which encode MSH6 p.Thr1100Met and @GENE$ @VARIANT$ in a family affected by colorectal cancer. All spouses were unrelated and unaffected by cancer. Genotypes: @GENE$ p.Thr1100Met (@VARIANT$; blue); MUTYH p.Tyr179Cys (Y179C; green); -, wild type.",7689793,MUTYH;8156,MSH6;149,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,T1100M;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,0
"RESULTS Mutations at the gap junction proteins Cx26 and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,Cx26;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The analysis included the complete coding regions and splice junctions of the following genes in the RAS-MAPK pathway: BRAF, @GENE$, KRAS, MAP2K1, MAP2K2, PTPN11, RAF1, and SOS1, as well as exon 2 of SHOC2. The DNA sequence was analyzed and compared to published genomic reference sequences. The result was confirmed by repeat sequence analysis on a newly prepared DNA sample. Multiple databases were queried to determine the novelty of the identified @GENE$ variant, including a proprietary GeneDx database of previously tested patients, Human Gene Mutation Database, dbSNP, and NCBI/Pubmed. Also, the variant was analyzed using the missense variant pathogenicity prediction software SIFT (Sorting Intolerant From Tolerant; http://sift.bii.a-star.edu.sg/) and POLYPHEN (Polymorphism Phenotyping; http://genetics.bwh.harvard.edu/pph/). RESULTS Molecular genetic testing of the RAS/MAPK pathway revealed a known pathologic heterozygous mutation in exon 12 of PTPN11 (@VARIANT$) and a novel missense variant in SOS1 (@VARIANT$; Fig. 3).",5101836,HRAS;55890,SOS1;4117,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis.         We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: 179260153C/T, refSNP ID rs4935; Chr5: 179260213G/A, rs4797; Chr5: 179264731T/C, rs10277; Ch5: @VARIANT$, rs1065154 ].",5868303,TIA1;20692,SQSTM1;31202,c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,179264915G/T;tmVar:c|SUB|G|179264915|T;HGVS:c.179264915G>T;VariantGroup:2;CorrespondingGene:8878;RS#:1065154,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,CDH23;11142,MYO7A;219,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (p.R559W) and @GENE$: @VARIANT$ (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.7942G > A;tmVar:c|SUB|G|7942|A;HGVS:c.7942G>A;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,1
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"SCUBE2 functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2).",6161649,VEGFR2;55639,RASA1;2168,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the @VARIANT$ mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of @GENE$ and/or @GENE$ expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism.",4470809,OPTN;11085,TBK1;22742,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, @VARIANT$, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.494C>T;tmVar:c|SUB|C|494|T;HGVS:c.494C>T;VariantGroup:185;CorrespondingGene:4647;RS#:111033174;CA#:278676,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Similarly, the @GENE$-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)p. Gln91Arg, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant p. Val969Ile of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. CDON seems to act similarly as CCDC88C through a digenic/oligogenic model to contribute to IHH. Case P06 had a missense variant in GADL1 (@VARIANT$), predicted as probably damaging. GADL1 expression is present during early brain development and is higher in olfactory bulb than that in other tissues, where is an active area for regeneration and migration of GnRH neurons. Consistent with this observation, case P06 was affected by anosmia, indicating that the function of @GENE$ might be involved in the etiology of IHH (Table 2).",8152424,CCDC88C;18903,GADL1;45812,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Ser221Cys;tmVar:p|SUB|S|221|C;HGVS:p.S221C;VariantGroup:5;CorrespondingGene:339896;RS#:775162663;CA#:2294666,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with @GENE$ @VARIANT$ and SETX p.T14I).",4293318,VAPB;36163,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Under the assumption of an autosomal recessive inheritance pattern, two variants were identified in @GENE$ (c.326_327insT, @VARIANT$ and c.7117C>T, p.(Gln2373*)) (Table 1, S3 Fig.). Segregation analysis showed that they were both present on the maternal allele (Figs. 1C-D). By analyzing for the presence of variants in genes implicated in intellectual disability, hearing impairment and inherited retinal disease, a heterozygous stop mutation in @GENE$ (@VARIANT$, p.(Ser512*)), a gene previously shown to be involved in autosomal recessive RP.",5967407,RP1L1;105870,C2orf71;19792,p.(Lys111Glnfs*27);tmVar:p|FS|K|111|Q|27;HGVS:p.K111QfsX27;VariantGroup:2;CorrespondingGene:94137;RS#:771427543;CA#:4625758,c.1535C>A;tmVar:c|SUB|C|1535|A;HGVS:c.1535C>A;VariantGroup:1;CorrespondingGene:388939;RS#:1293811678,1
"As a truncated germline @GENE$ variant has not been reported in humans, c.1891G>T (@VARIANT$) in patient AVM312 was classified as likely pathogenic and EGFR as a candidate gene due to the vital role of EGFR in EGF and VEGF signalling.  Recurrent biallelic damaging variants To assess the possibility of a recessive mode of inheritance, we investigated all homozygous and compound heterozygous variants with either a recurrent or LoF allele. Compound heterozygous variants in @GENE$, DSCAM and PTPN13 were retained. In two unrelated patients, AVM106 and AVM285, identical compound heterozygous variants were identified in DSCAML1: c.5783G>A (@VARIANT$) and c.4574G>A (p.Arg1525His), each inherited from heterozygous carrier parents (table 2).",6161649,EGFR;74545,DSCAML1;79549,p.Glu631Ter;tmVar:p|SUB|E|631|X;HGVS:p.E631X;VariantGroup:8;RS#:909905659,p.Arg1928His;tmVar:p|SUB|R|1928|H;HGVS:p.R1928H;VariantGroup:5;CorrespondingGene:57453;RS#:1212415588,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: c.1675C > T (p.R559W) and PKHD1: @VARIANT$ (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.7942G > A;tmVar:c|SUB|G|7942|A;HGVS:c.7942G>A;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,0
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (@VARIANT$), SNAI2 (@VARIANT$) and @GENE$ (c.101T>G) genes.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be @GENE$, DFNB3, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in @GENE$ (WFS1) (NM_001145853) according to TES.",4998745,DFNB7/11;23670,Wolfram syndrome 1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,ubiquilin-2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother.",8152424,DCAF17;65979,DMXL2;41022,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"Both SSPIDER and INTERPROSURF analysis (Figure S4) suggest functional importance for @VARIANT$; and SIFT predicts a deleterious effect for p.Ala253Thr. Although p.Ala253Thr did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, @GENE$, PROK2, PROKR2, TAC3, TACR3, GNRHR, @GENE$, or KISS1R.",3888818,FGFR1;69065,GNRH1;641,Ala253;tmVar:p|Allele|A|253;VariantGroup:3;CorrespondingGene:26012;RS#:142726563,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"The minimum free energy (MFE) of @GENE$ @VARIANT$ increased, which thus lead to a reduction of structural stability. However, @GENE$ @VARIANT$ showed no significant influence on the RNA structure (Figure 4c,d).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Four genes (including @GENE$, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-@VARIANT$ (p.Ala1012Val) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,AGXT2;12887,SCAP;8160,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, @VARIANT$, p.Tyr27His), MBD5 (NM_018328.4, @VARIANT$, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0
"Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and @GENE$ mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,EphA2;20929,SLC26A4;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"Her mother with @VARIANT$ in COL4A5 and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
" In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).      In patient AVM467, the de novo heterozygous missense variant @VARIANT$ (p.Gly226Ser) was identified in @GENE$ (table 1).",6161649,CDH2;20424,IL17RD;9717,c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,c.676G>A;tmVar:c|SUB|G|676|A;HGVS:c.676G>A;VariantGroup:5;CorrespondingGene:23592;RS#:1212415588,0
"A rare variant in @GENE$, @VARIANT$; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/@GENE$ (c.1632G>A; @VARIANT$) pathogenic missense alteration was identified.",7696449,AMH;68060,FOG2;8008,c.428C>T;tmVar:c|SUB|C|428|T;HGVS:c.428C>T;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,p.Met544Ile;tmVar:p|SUB|M|544|I;HGVS:p.M544I;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. We found that mutations in the two genes segregated in the family and that the unaffected parents were healthy and carried heterozygous mutations in both @GENE$ and @GENE$, consistent with an autosomal-recessive mode of inheritance.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for @GENE$ (Cx26) and connexin 31 (Cx31) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and @GENE$ have overlapping expression patterns in the cochlea.",2737700,connexin 26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"The @VARIANT$ (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Total Serum Ig, clinical score and TNFRSF13B/@GENE$ @VARIANT$ and @GENE$ @VARIANT$ genotype for each family member, as indicated.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T161fsX191;tmVar:p|FS|T|161||191;HGVS:p.T161fsX191;VariantGroup:5;CorrespondingGene:6929,1
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Sequence alterations were detected in the COL6A3 (@VARIANT$), @GENE$ (@VARIANT$), @GENE$ (rs138172448), and DES (rs144901249) genes.",6180278,RYR1;68069,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Interestingly, four of these @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,1
"The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the SLC20A2 mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Here, we identified an individual (ID139) who carried a missense variant @VARIANT$ (p.Asp813Glu) in CDKL5 on the X chromosome. This female was referred at the age of 3 years. Her developmental history indicates the manifestation of arrested development at the age of 1 year. At 3 years of age, the family reported sleeping difficulties; at 8 years old, the family reported obesity, a lack of motor coordination, and profound hyperactivity. The variant in @GENE$ was predicted to be deleterious using SIFT and MutationTaster and was present in the ExAC database at a rate of 2 x 10-5. This variant appears to be a plausible cause of autism and developmental regression in ID139.    Genetic variants in GRIN2A are a major cause of Landau Kleffner syndrome. Patients ID090 and ID113 carried the same variant in @GENE$ (see above). In addition, ID031 carried a different variant, GRIN2A @VARIANT$ (p.Ala302Ser), which was absent from the ExAC database and present in the gnomAD database at a rate of 7.98 x 10-6.",7463850,CDKL5;55719,GRIN2A;645,c.1387A > G;tmVar:c|SUB|A|1387|G;HGVS:c.1387A>G;VariantGroup:8;CorrespondingGene:6792;RS#:770224409;CA#:10360381,c.904G > T;tmVar:c|SUB|G|904|T;HGVS:c.904G>T;VariantGroup:10;CorrespondingGene:2903,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,GJB2;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, @VARIANT$ (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father).",3975370,IL10RA;1196,NOD2;11156,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,1
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The DUSP6 gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"          REEP4 Variant in African-American Pedigree with @GENE$ and BSP. (a) Family 10908 with BSP+ and BSP. Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with BSP+ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates                TOR2A missense variant A TOR2A nonsynonymous SNV (c.568C>T [NM_130459.3], @VARIANT$ [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,BSP+;3644,REEP4;11888,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"RESULTS Molecular genetic testing of the RAS/MAPK pathway revealed a known pathologic heterozygous mutation in exon 12 of PTPN11 (@VARIANT$) and a novel missense variant in SOS1 (@VARIANT$; Fig. 3). The patient's mother's echocardiogram was normal, but she has repeatedly declined parental targeted mutation analysis. The father has declined repeated requests for echocardiography and molecular genetic testing. The parents declined requests for photographs; examination did not suggest a RASopathy.     DISCUSSION Our patient has overlapping clinical features of @GENE$-related NS-ML and @GENE$-related NS (Table I).",5101836,PTPN11;2122,SOS1;4117,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,1
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Our results indicate that the novel @GENE$-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNE1;3753,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB6;4936,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,CHD7;19067,DCC;21081,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"    Family 4 with @GENE$ and @GENE$ mutations. (A) The pedigree indicates that the proband (II:1) was a simplex case of FTA. She was the only affected individual in the family. The DNA sequencing chromatograms from the proband show two LRP6 and one WNT10A heterozygous mutations. While both LRP6 variants, p.(@VARIANT$) and p.(Asn1075Ser), were inherited from her father, the WNT10A mutation, @VARIANT$ was maternally derived.",8621929,LRP6;1747,WNT10A;22525,Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"The novel truncated variant in @GENE$ was not found in our ""in-house"" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The c.229C>T (p.R77C) variant in S100A3 and c.238-241delATTG (@VARIANT$) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.             Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, S100A13 and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder. Consequences of the S100A3 c.229C>T and S100A13 variants The S100A3 c.229C>T variant resulted in an @VARIANT$ within the second of the two EF-hand calcium binding motifs in the protein.",6637284,S100A13;7523,S100A3;2223,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,arginine to cysteine substitution at residue 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (@VARIANT$; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in S100A13. Mutation name is based on the full-length @GENE$ (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and @GENE$-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"In patient AVM359, one heterozygous VUS (@VARIANT$ [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling.",6161649,ENG;92,SCUBE2;36383,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Importantly, he had no coexistent mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, @GENE$, GNRHR, GNRH1, or KISS1R. The second patient (KS male C7) had a heterozygous c.757G>A (@VARIANT$) mutation (Figure 1; Table 1) affecting a completely conserved Ala253 residue (Figures @GENE$). Using multiple sequence alignment (ESPRESSO), a protein model for the N-terminus was constructed. Both SSPIDER and INTERPROSURF analysis (Figure S4) suggest functional importance for Ala253; and SIFT predicts a deleterious effect for p.Ala253Thr. Although p.Ala253Thr did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously.",3888818,KAL1;55445,S1-4;7069;5707;6187;6188;6192,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Circles, female; squares, male; gray, TNFRSF13B/@GENE$ @VARIANT$ mutation; blue TCF3 T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,TOR2A;25260,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"    A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Mutations in genes involved in WNT/beta-catenin signaling, including AXIN2 WNT10A, @GENE$, @GENE$, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(@VARIANT$), @VARIANT$, and p.(Asn1075Ser).",8621929,WNT10B;20721,LRP6;1747,Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.(Ala754Pro);tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes.     ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The @VARIANT$ (c.1045G>A) mutation in exon 9 of EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of WNT10A were detected.",3842385,EDA;1896,WNT10A;22525,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,0
"We did not find a mutation in @GENE$ in any of the individuals carrying a mutation in PROKR2 or @GENE$, either. However, one of the patients heterozygous for the @VARIANT$ mutation in PROKR2 (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in KAL1 exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,FGFR1;69065,PROK2;9268,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for connexin 26 (@GENE$) and @GENE$ (Cx31) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,connexin 31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"  Digenic inheritances of GJB2/MITF and @GENE$/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"In AS patient IID27, the two mutations in @GENE$ and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation @VARIANT$ in COL4A5, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a).",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,1
"In our studied family, SH107-225 with profound SNHL carried @VARIANT$ in @GENE$ and a de novo variant, p.R341C in MITF. DFNB1 as a molecular etiology was excluded from this subject, while digenic inheritance of SNHL can be proposed for this subject because the pathogenic potential of @VARIANT$ was strongly supported by significant conservation of the p.R341 residue among various species and by the absence of this variant among the 666 control chromosomes from normal hearing control subjects. Based on the varying degrees of audiologic phenotypes of MITF-related WS2, including single side deafness, bilateral profound SNHL of SH107-225 may have resulted from the additive effect of single heterozygous c.235delC of GJB2, and the @GENE$ mutation through digenic inheritance.",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in @GENE$. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX @VARIANT$).",4293318,TARDBP;7221,ATXN2;2234,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,VAPB;36163,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
The @GENE$ gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).,8446458,DUSP6;55621,SEMA7A;2678,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, @VARIANT$) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"The @GENE$ and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,SETDB1;32157,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-@GENE$ @VARIANT$, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,pendrin;20132,EphA2;20929,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the @GENE$ [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).                   The PCDH15 variant [NM_033056: @VARIANT$; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892).",6053831,PCDH15;23401,USH1G;56113,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,c.3101G > A;tmVar:c|SUB|G|3101|A;HGVS:c.3101G>A;VariantGroup:2;CorrespondingGene:124590,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"    A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (@VARIANT$; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, was identified in patient #3. BBS1, BBS2 and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of BBS2 and BBS7 lie in this portion. The variant in BBS7 is noteworthy, since very few Bardet-Biedl cases are reported in the literature. Indeed, only 35 variants in this gene are listed in the Human Gene Mutation Database (HGMD, https://portal.biobase-international.com/cgi-bin/portal/login.cgi). A homozygous substitution c.1235G > T in @GENE$, leading to p.(Cys412Phe), was also identified in an affected sibling of proband #12.",6567512,BBS7;12395,BBS6;10318,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.",3842385,WNT10A;22525,EDA;1896,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
   Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the @GENE$ gene and in exon 4 (@VARIANT$; p.Pro291Arg) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the GCK variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B).,8306687,GCK;55440,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 @VARIANT$, SCRIB @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of @GENE$, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of @GENE$, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,CELSR1;7665,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"    A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and @GENE$ @VARIANT$ with SETX @VARIANT$ and @GENE$ p.T14I).,4293318,TAF15;131088,SETX;41003,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"(c, d) SCN5A @VARIANT$ showed no significant influence on the RNA structure, and the MFE value of @GENE$ p.R1865H mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type @GENE$ (Table 3), KCNH2 @VARIANT$ showed a decreasing trend in molecular weight and increasing instability.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"While tagged versions of EphA2 G355R and EphA2 @VARIANT$ were effectively precipitated with Fc-fusion ephrin-A1 compared to EphA2 WT, Fc-fusion ephrin-B2 failed to pull down @GENE$ G355R and T511M (Fig. 7a). Consistently, internalization of EphA2 G355R and EphA2 T511M with pendrin induced by ephrin-B2 but not ephrin-A1 was suppressed (Fig. 7b, c). On the other hand, the mutated forms of EphA2 did not affect their ability to bind to pendrin (Fig. 7d).        Discussion Proper and polarized localization of transporters in cells is essential for their function. Various previously identified pendrin mutations cause @GENE$ cytoplasmic localization. A subset of these mutations, such as @VARIANT$, are known to cause mis-folding of the protein, leading to accumulation in the endoplasmic reticulum.",7067772,EphA2;20929,pendrin;20132,T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,H723R;tmVar:p|SUB|H|723|R;HGVS:p.H723R;VariantGroup:10;CorrespondingGene:5172;RS#:121908362;CA#:253307,0
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 156 to Cys.",3842385,EDA;1896,WNT10A;22525,Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB6;4936,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"Colocalization of @GENE$ and pro-COL1A1 was significantly reduced in fibroblasts with heterozygous and homozygous mutations in both @GENE$ and MAN1B1 (P < 0.001, ANOVA) when compared with colocalization in wild-type and SEC23A heterozygous cells (Fig. 6, cf. I,L and C,F) (Table 5; Supplemental Fig. S6). Thus, the presence of combined mutations in SEC23A and MAN1B1 results in reduced pro-COL1A1 in the ER. Colocalization of pro-COL1A1 with endoplasmic reticulum (ER) was reduced in patient fibroblasts. Protein disulfide isomerase (PDI) (green; A,D,G,J), a marker of ER lumen, and intracellular pro-COL1A1 (red; B,E,H,K) were visualized using immunofluorescence microscopy. Merged images showing pro-COL1A1 colocalization with PDI in wild-type (Wt) (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ MAN1B1R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double homozygous (L) fibroblasts.",4853519,PDI;55495,SEC23A;4642,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and TAF15 p.R408C with @GENE$ @VARIANT$ and SETX p.T14I).,4293318,VAPB;36163,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Among the 8 novel variants, 4 were classified as P (@VARIANT$ and @VARIANT$ in @GENE$, p.T803fs in @GENE$) or LP (p.D137E in DUOX2), the other were classified as VUS.",7248516,TSHR;315,DUOX2;9689,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,p.K618*;tmVar:p|SUB|K|618|*;HGVS:p.K618*;VariantGroup:4;CorrespondingGene:7253,0
"This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2).",6161649,ENG;92,BMP;55955,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Proband 17 inherited @GENE$ @VARIANT$ and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 @VARIANT$ variant.",8152424,CHD7;19067,CDON;22996,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Four potential pathogenic variants, including @GENE$ p.R1865H (NM_001160160, c.G5594A), LAMA2 @VARIANT$ (NM_000426, c.G2881A), @GENE$ @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,SCN5A;22738,KCNH2;201,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Four genes (including AGXT2, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-@VARIANT$ (p.Ala1012Val) and @GENE$-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,SCAP;8160,AGXT2;12887,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"(A) Patient with homozygous variants in both ANO5 and @GENE$ genes. NGS reads indicated the identification of homozygous missense pathogenic variants @VARIANT$ (p.R758C) and c.850C>T (R284C) in ANO5 and SGCA genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in ANO5 gene and one pathogenic variant in COL6A2 gene indicating multiple gene contributions for an unusual presentation. His mother, a 40-year-old female with one pathogenic variant each in ANO5 and @GENE$ shows unspecified myopathy with elevated creatine phosphokinase (CPK).         Deep intronic variant in DYSF gene Recently, we characterized a deep intronic mRNA splice-altering pathogenic variant @VARIANT$ in DYSF gene that inserts a novel 177 bp pseudoexon at the exon 44-45 junction.",6292381,SGCA;9,COL6A2;1392,c.2272C>T;tmVar:c|SUB|C|2272|T;HGVS:c.2272C>T;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,c.4886 + 1249G>T;tmVar:c|SUB|G|4886+1249|T;HGVS:c.4886+1249G>T;VariantGroup:10;CorrespondingGene:8291;RS#:886042110;CA#:10603819,0
"In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in @GENE$ (OMIM 612981; rs146322628, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in @GENE$ (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and ARHGEF19 (OMIM 612496; @VARIANT$, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,IMP4;68891,UBR4;10804,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,rs144638812;tmVar:rs144638812;VariantGroup:0;CorrespondingGene:128272;RS#:144638812,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, @VARIANT$) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"Five subjects (R279, R410, R465, R469 and R470) carried pathogenic and deleterious variants in genes known to affect glycogen metabolism (GBE1, PYGM), FAO (ACADVL and CPT2), fatty acid and amino acid catabolism (PCCB), oxidative phosphorylation (ELAC2, NDUFA6, NDUFA10 and NUBPL), mitochondrial matrix enzymes (@GENE$ and TIMM50). Two subjects (R302 and R462) had variants in genes involved in Ca 2+ regulation (RYR1 and CACNA1S), glycogen metabolism (GBE1 and @GENE$) and oxidative phosphorylation (NDUFS8). Mutations in PHKA1 cause Glycogen Storage Disease type IX, X-linked phosphorylase kinase (PHK) enzyme deficiency, characterized by high muscle glycogen content and severe reduction of muscle PHK activity. However, none of these signs were evident from metabolic work of the patient with PHKA1 @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and NDUFS8 @VARIANT$ variants remain unknown.",6072915,OAT;231,PHKA1;1981,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0
(b) A sequence chromatogram showing the @GENE$ (@VARIANT$;p.R85C) mutation. (c) A sequence chromatogram showing the @GENE$ (c.1306A>G;@VARIANT$) mutation.,5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of DUOX1 (c.1823-1G>C) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX2;9689,DUOX1 and -2;53905;50506,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Her mother with c.1339 + 3A>T in @GENE$ and her father with a missense mutation @VARIANT$ in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"These two individuals were heterozygous carriers of p.R1141X mutation in @GENE$ and @VARIANT$ in @GENE$. Since heterozygous carriers of @VARIANT$ in ABCC6 alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance.",2900916,ABCC6;55559,GGCX;639,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 @VARIANT$ and @GENE$ @VARIANT$). One patient (f93-80) had a novel @GENE$ missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T).",5887939,SCRIB;44228,PTK7;43672,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,LQT6;71688,LQT2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (@VARIANT$), inherited digenically with a homozygous DUOX2 nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of DUOX1 (c.1823-1G>C) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1;68136,DUOX1 and -2;53905;50506,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,0
"Four potential pathogenic variants, including SCN5A @VARIANT$ (NM_001160160, c.G5594A), LAMA2 @VARIANT$ (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. @GENE$ gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database).",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a @VARIANT$ of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of @GENE$, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and @VARIANT$ was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,CELSR1;7665,SCRIB;44228,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"Furthermore, we ascertained the interactions of TEK and @GENE$ by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), @GENE$ (p.Q214P)::CYP1B1 (@VARIANT$), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,CYP1B1;68035,TEK;397,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"On the other hand, mutant GFP-@GENE$ @VARIANT$ and R368H showed perturbed interaction with HA-@GENE$. The residues E103, I148, and @VARIANT$ lie in the N-terminal extracellular domain of TEK (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214;tmVar:p|Allele|Q|214;VariantGroup:10;CorrespondingGene:7010,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"This indicates that neither @VARIANT$ in GJB2 nor p.D771N in WFS1 contributed to SNHL in SH60-136 and that p.R143W in GJB2 was an incidentally detected variant in this subject. @GENE$ = gap junction protein beta 2, SNHL = sensorineural hearing loss, WFS1 = wolfram syndrome 1.             Single Heterozygous GJB2 Mutant Allele Possibly Contributing to Deafness via Digenic Inheritance: Double Heterozygosity with Additional Mutation in Other Deafness Genes (Group II) Interestingly, two subjects (SH107-225 and SH175-389) showed double heterozygosity for a GJB2 mutation and another likely pathogenic mutation in another deafness gene. We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, @VARIANT$, in one of the c.235delC carriers (SH107-225) (Figure 4A).",4998745,GJB2;2975,MITF;4892,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"A new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, @VARIANT$, was identified in patient #3. @GENE$, BBS2 and BBS7 share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype.",6567512,BBS7;12395,BBS1;11641,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"      WES revealed heterozygous mutations in two genes known to affect hypothalamic and pituitary development: @VARIANT$;p.R85C in @GENE$ (MIM 607123; NM_144773.2; rs141090506) inherited from an unaffected mother and c.1306A>G;p.I436V in @GENE$ (MIM 606417; NM_018117.11; @VARIANT$) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1).",5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,rs34602786;tmVar:rs34602786;VariantGroup:3;CorrespondingGene:55717;RS#:34602786,1
"(C) The @GENE$ mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant EDA allele from his mother; WNT10A mutations in the parents could not be analyzed. (D) The EDA mutation @VARIANT$ and @GENE$ mutation c.637G>A were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis. (E) The EDA mutation c.466C>T and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in EDA and @VARIANT$ in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ @VARIANT$), 2F07 (CELSR1 @VARIANT$ and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A).",5887939,PRICKLE4;22752,DVL3;20928,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (@VARIANT$, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,g.27546T>A;tmVar:g|SUB|T|27546|A;HGVS:g.27546T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"The DNA sequencing chromatograms from the proband show two @GENE$ and one @GENE$ heterozygous mutations. While both LRP6 variants, p.(Ser127Thr) and p.(@VARIANT$), were inherited from her father, the WNT10A mutation, @VARIANT$ was maternally derived.",8621929,LRP6;1747,WNT10A;22525,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"The @GENE$ variant is designated as @VARIANT$ and reported at allele frequencies of 0.0071 in ExAC, 0.0016 in TGP, and 0.0068 in GO-ESP (accessed January 23, 2018). We examined the genotype data in the TGP to determine whether these variants coincide in controls. None of 2,504 self-declared healthy individuals in TGP has both TIA1, c.1070A > G (p.Asn357Ser) and @GENE$, c.1175C > T (@VARIANT$).",5868303,TIA1;20692,SQSTM1;31202,rs116621885;tmVar:rs116621885;VariantGroup:5;CorrespondingGene:7072;RS#:116621885,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (@VARIANT$), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (@VARIANT$) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, TG, @GENE$, @GENE$, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,DUOX2;9689,DUOXA2;57037,p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0
"The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(Ser123Thr), and a second variant in PKD2, p.(Arg872Gly). Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(@VARIANT$) variant in @GENE$, while only one fetus inherited the p.(Arg872Gly) @GENE$ variant.",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser872Gly;tmVar:p|SUB|S|872|G;HGVS:p.S872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061,0
"   Conservation analyses at the mutant sites of @GENE$ and KCNH2 protein. SCN5A p.R1865 and @GENE$ p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for SCN5A and KCNH2 mutations. KCNH2 p.307_308del and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A p.R1865H. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus lead to a reduction of structural stability. However, SCN5A @VARIANT$ showed no significant influence on the RNA structure (Figure 4c,d).",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in @GENE$. The mutations in @GENE$, USH1G and USH2A were not found in 666 control alleles.",3125325,USH1G;56113,MYO7A;219,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"(E) The EDA mutation c.466C>T and @GENE$ mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in @GENE$ and @VARIANT$ in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,WNT10A;22525,EDA;1896,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"To investigate the effects of one candidate variant on mutant @GENE$ function, Western blotting and coimmunofluorescence were used to assess binding capacity, and leptomycin B exposure along with immunofluorescence was used to assess nuclear localization. Results: We describe a child who presented in infancy with combined pituitary hormone deficiencies and whose brain imaging demonstrated a small anterior pituitary, ectopic posterior pituitary, and a thin, interrupted stalk. WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father.",5505202,WDR11;41229,PROKR2;16368,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"  Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in @GENE$ (p.Pro392Leu) and a variant in @GENE$ (@VARIANT$). At the time of this report, only a single prior myopathy case with the same genetic variants has been reported, but the clinical and myopathological features were not illustrated. There are also two further cases of MRV having the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), one of whom was previously reported as having a SQSTM1-MRV.",5868303,SQSTM1;31202,TIA1;20692,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"On the contrary, the functionality of the @GENE$-p.R583H channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. @GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-@VARIANT$, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for @GENE$ (Cx26) and connexin 31 (@GENE$) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,connexin 26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
"The @VARIANT$ mutation would be predicted to generate a nonfunctional @GENE$ enzyme, and its digenic inheritance alongside the homozygous @GENE$ @VARIANT$ will likely result in complete absence of functional DUOX isoenzyme in our patients.",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,1
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,CACNA1A;56383,GNA14;68386,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Both mutations are novel and whilst a different mutation, @VARIANT$, has been reported in @GENE$, further evidence to support the pathogenicity of @VARIANT$ is lacking. The siblings we describe with the @GENE$ P291fsinsC and HNF4A R127W mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic.",4090307,HNF4A;395,HNF1A;459,R80W;tmVar:p|SUB|R|80|W;HGVS:p.R80W;VariantGroup:2;CorrespondingGene:3172,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Furthermore, this @GENE$-@VARIANT$ mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (p.R1193Q, @VARIANT$) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This @GENE$-R1193Q variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,rs41261344;tmVar:rs41261344;VariantGroup:7;CorrespondingGene:6331;RS#:41261344,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and TAF15 p.R408C with SETX @VARIANT$ and @GENE$ p.T14I).,4293318,VAPB;36163,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.Arg106Pro) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 @VARIANT$ and @GENE$ @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (c.1892C>T).",5887939,SCRIB;44228,CELSR2;1078,c.8282C>T;tmVar:c|SUB|C|8282|T;HGVS:c.8282C>T;VariantGroup:4;CorrespondingGene:9620;RS#:144039991;CA#:10292903,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: c.1675C > T (p.R559W) and PKHD1: c.7942G > A (@VARIANT$), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,p.G2648S;tmVar:p|SUB|G|2648|S;HGVS:p.G2648S;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,0
"To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and @GENE$: c.535C>A, @VARIANT$) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (@GENE$: @VARIANT$ and p.(H395N); PITX2: p.(P179T)).",6338360,PITX2;55454,FOXC2;21091,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, @VARIANT$, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.223delG;tmVar:c|DEL|223|G;HGVS:c.223delG;VariantGroup:77;CorrespondingGene:4647;RS#:876657415,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and @GENE$/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI @VARIANT$ mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"RESULTS Mutations at the gap junction proteins @GENE$ and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Thus, combined mutations in SEC23A and MAN1B1 result in retention of pro-@GENE$ in the Golgi. Colocalization of pro-COL1A1 with trans-Golgi was increased in patient fibroblasts. TGN38 (green; A,D,G,J), a marker of trans-Golgi, and intracellular pro-COL1A1 (red; B,E,H, K) were visualized using immunofluorescence microscopy. Merged images showing pro-COL1A1 colocalization with TGN38 in wild-type (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ MAN1B1R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ @GENE$R334C/@VARIANT$ double-homozygous (L) fibroblasts.",4853519,COL1A1;73874,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-@VARIANT$ heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"        @GENE$ (PROK2) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the PROKR2 and @GENE$ genes, which can be passed down through autosomal dominant or oligogenic inheritance. In our study, 40% of patients developed PROK2/PROKR2 variants, which was significantly higher than the 9% in the Caucasian population. Most of them were missense variants in patients with a nonobvious phenotype. In our study, only one patient had a splicing mode variant; the rest of the patients had missense variants. Some patients exhibited olfactory dysosmia and obesity, which was consistent with the clinical manifestations of extreme obesity in patients with PROKR2 variants reported in previous studies. Two novel variants of the PROK2 gene were found in patients with anosmia, obvious small phallus, and low levels of sex hormones. @VARIANT$ might affect the normal splicing of exons in the PROK2 gene, and the novel variant c.306G > C (@VARIANT$) was predicted to be harmful by multiple software programs.",8796337,Prokineticin-2;9268,PROKR2;16368,c.223 - 4C > A;tmVar:c|SUB|C|223-4|A;HGVS:c.223-4C>A;VariantGroup:21;CorrespondingGene:60675,p. Arg102Ser;tmVar:p|SUB|R|102|S;HGVS:p.R102S;VariantGroup:20;CorrespondingGene:3730,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in @GENE$ were identified (online supplementary table S2).",6161649,RASA1;2168,TIMP3;36322,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,1
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"    Sanger sequencing Sanger sequencing was performed on available samples for confirmation of @GENE$ and @GENE$ variants in family members to perform segregation analysis. Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (p.N382S/@VARIANT$) and MYO6 (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,VPS13C;41188,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, @VARIANT$), LAMA2 p.A961T (NM_000426, c.G2881A), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS. The mutations of KCNH2 @VARIANT$ and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,KCNH2;201,SCN5A;22738,c.G5594A;tmVar:c|SUB|G|5594|A;HGVS:c.5594G>A;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
" @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein. However, the two rare FUS variants (@VARIANT$ and P106L) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein. Although the majority of FUS mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging.       In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (K631del) were identified in our patient cohort. The patient (#90u) carrying the novel @VARIANT$ deletion was a 37-year-old patient who also showed symptoms of frontotemporal dementia (FTD). This is in line with the data from previous studies; according to which, TBK1 is a causative gene of ALS-FTD. The @GENE$ R261H variant was also present in this patient.",6707335,FUS;2521,NEK1;14376,Y25C;tmVar:p|SUB|Y|25|C;HGVS:p.Y25C;VariantGroup:12;CorrespondingGene:2521;RS#:141516414;CA#:8023442,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,FUS;2521,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TOR2A;25260,DNAH17;72102,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and @VARIANT$ localized to the carbonic anhydrases subunits, named the CA domain of @GENE$, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,SCRIB;44228,CELSR1;7665,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, @VARIANT$, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"We provide evidence that mutations in the Cx26 and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"  This patient also was found to have a novel, heterozygous @GENE$ nonsense mutation p.Trp275X not seen in 180 controls (Figure 1C; Table 1). @VARIANT$ lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this G-protein coupled receptor, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, TAC3, KAL1, GNRHR, GNRH1, or @GENE$. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (@VARIANT$) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;p.Thr478Ala from NP_056352).",3888818,TACR3;824,KISS1R;11411,Trp275;tmVar:p|Allele|W|275;VariantGroup:1;CorrespondingGene:6870;RS#:144292455,p.Thr480Ala;tmVar:p|SUB|T|480|A;HGVS:p.T480A;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,0
"        Ebermann et al. described a USH2 patient with ""digenic inheritance."" a heterozygous truncating mutation in @GENE$, and a truncating heterozygous mutation in PDZ domain-containing 7 (PDZD7), which is reported to be a cause of USH. Our USH1 patient (Case #4) had segregated MYO7A:@VARIANT$ and @GENE$:@VARIANT$. Molecular analyses in mouse models have shown many interactions among the USH1 proteins.",3949687,GPR98;19815,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (c.229C>T; @VARIANT$) and d) the c.238-241delATTG (@VARIANT$) in S100A13. Mutation name is based on the full-length @GENE$ (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0
The @GENE$ gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).,8446458,DUSP6;55621,SEMA7A;2678,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,1
"The proband (arrow, II.2) is heterozygous for both the @GENE$ T168fsX191 and @GENE$/TACI C104R mutations. Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI @VARIANT$ mutations are shown.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (@VARIANT$), inherited digenically with a homozygous @GENE$ nonsense mutation (c.1300 C>T, @VARIANT$).",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,1
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys.",3842385,WNT10A;22525,EDA;1896,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"As shown in Supplementary Fig. 3a, the mutant HA-@GENE$ proteins E103D and @VARIANT$ exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-@GENE$ @VARIANT$ and R368H showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Finally, for Case 7 and her father, a previously reported ZFPM2/FOG2 (@VARIANT$; p.Met544Ile) pathogenic missense alteration was identified. No additional variants in other genes associated with testicular development and DSD were identified by our panel in Cases 3, 5 and 6. We were not able to further analyze Case 4 because of a lack of sample availability. 2.3. Transcription Activity and Protein Expression Testing of Novel NR5A1 Variants To study the impact of the three novel missense variants of NR5A1 on transactivation activity of regulated genes, HEK293 cells were co-transfected with WT or mutant NR5A1 expression vectors and three different promoter reporter constructs essential for steroid and sex hormone biosynthesis. All three novel @GENE$ variants had significantly reduced activity on the CYP17A1 reporter compared to WT (Figure 2A). These results were confirmed for the @VARIANT$ and Cys30Ser variants when using the reporters for CYP11A1 and @GENE$ (Figure 2B,C).",7696449,NR5A1;3638,HSD17B3;20089,c.1632G>A;tmVar:c|SUB|G|1632|A;HGVS:c.1632G>A;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,His24Leu;tmVar:p|SUB|H|24|L;HGVS:p.H24L;VariantGroup:4;CorrespondingGene:6736;RS#:1262320780,0
"@GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-@VARIANT$, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"4.4. Cell Culture and Heterologous Expression Chinese hamster ovaries (CHO-K1, American Type Culture Collection) were grown in F-12 HAM nutrient mixture medium (11765-054, ThermoFischer Scientific Inc., Waltham, MA, USA) supplemented with 10% fetal bovine serum (ThermoFisher Scientific Inc., Waltham, MA, USA), 2 mM l-glutamine, 50 U/mL penicillin, and 50 mug/mL streptomycin (Sigma, St. Louis, MO, USA) in a humidified 5% CO2 atmosphere at 37  C. Cells were transfected using Fugene 6 (Roche, Mannheim, Germany) in 21 cm2 dishes with 1 mug (KCNQ1-WT or @GENE$-@VARIANT$) or 1.5 mug (KCNH2-WT or @GENE$-@VARIANT$) plasmid/dish in transient transfection experiments.",5578023,KCNQ1;85014,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,1
"Our data are consistent with those of Rafiq et al. and Rymen et al., as we found reduced MAN1B1 protein levels and glycosylation defects in patients double homozygous for the @VARIANT$ @GENE$ and the @VARIANT$ @GENE$ mutations.",4853519,MAN1B1;5230,SEC23A;4642,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,12000 G>C;tmVar:g|SUB|G|12000|C;HGVS:g.12000G>C;VariantGroup:14;CorrespondingGene:10484,1
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, PROKR2, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROK2;9268,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and PITX2: c.535C>A, @VARIANT$) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and @VARIANT$; PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C @VARIANT$).",8152424,FGFR1;69065,DCC;21081,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ p.R148Q, @GENE$ @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,PTK7;43672,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
" @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Using SIFT and PolyPhen, the @VARIANT$ variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and c.353A > G (@VARIANT$) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"In patient AVM028, the de novo heterozygous missense variant c.311T>C (@VARIANT$), in the functional inhibition of zinc metalloproteinases (NTR) domain, was identified in TIMP3 (table 1), which encodes a tissue metalloproteinase inhibitor. TIMP3 inhibits VEGF-mediated angiogenesis by blocking VEGF/VEGFR2 binding (figure 3), a function considered independent of metalloproteinase inhibition and unique to TIMP3 compared with other known TIMPs.  In patient AVM359, the de novo heterozygous missense variant @VARIANT$ (p.Cys531Tyr) was identified in SCUBE2 (table 1), which encodes a membrane-associated multidomain protein. The variant is predicted to affect a conserved site (SIFT=0, PolyPhen2=1, GERP++=5.68, CADD=24.6). SCUBE2 forms a complex with VEGF and @GENE$ and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The c.1592G>A (p.Cys531Tyr) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies.",6161649,VEGFR2;55639,SCUBE2;36383,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,KAL1;55445,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"A rare variant in @GENE$, @VARIANT$; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported @GENE$/FOG2 (c.1632G>A; @VARIANT$) pathogenic missense alteration was identified.",7696449,AMH;68060,ZFPM2;8008,c.428C>T;tmVar:c|SUB|C|428|T;HGVS:c.428C>T;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,p.Met544Ile;tmVar:p|SUB|M|544|I;HGVS:p.M544I;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"(A) In addition to @VARIANT$ in GJB2, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus.",4998745,MITF;4892,GJB6;4936,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous @GENE$ E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"The functional studies, via the exogenous expression approach, revealed that the CACNA1C-@VARIANT$ mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of CACNA1C-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation. Conclusions Our results demonstrated that the loss-of-function @GENE$-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Digenic inheritance of @GENE$ and @GENE$ variants in familial colorectal cancer Abstract We describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding MSH6 @VARIANT$ and MUTYH @VARIANT$ in, at least, three CRC patients diagnosed before 60 years of age.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,1
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and @GENE$ @VARIANT$).",4293318,DCTN1;3011,SETX;41003,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and HNF4A R80Q. Both mutations are novel and whilst a different mutation, R80W, has been reported in HNF4A, further evidence to support the pathogenicity of E508K is lacking. The siblings we describe with the HNF1A P291fsinsC and @GENE$ @VARIANT$ mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic.",4090307,HNF1A;459,HNF4A;395,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,GJB3;7338,Cx26;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ @VARIANT$ (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization.",8739608,LAMA2;37306,KCNH2;201,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"Sequestosome-1 (@GENE$, chr.5) is a scaffolding protein involved in multiple cellular processes, including apoptosis, cell survival, and autophagy. Its numerous domains allow SQSTM1 to serve as a frame for multiprotein complexes and regulator of ubiquitinated protein turnover. SQSTM1 mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK @VARIANT$ (~70%). No significant change was observed with HA-TEK G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. The residues E103, I148, and Q214 lie in the N-terminal extracellular domain of @GENE$ (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Only three variants were homozygous in three patients: (1) DUOX2: @VARIANT$ (p.M927V) in one patient, (2) @GENE$:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: @VARIANT$ (p.Y138X) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"(a, b) Compared with wild-type KCNH2, the structure of KCNH2 @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of @GENE$ p.307_308del increased, which thus led to a reduction of structural stability. (c, d) @GENE$ p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A @VARIANT$ mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Both of which suggest that wild-type splicing would be affected     A recent study (Mazen et al., 2016) identified pathogenic variants in @GENE$ and MAP3K1 in an individual with 46,XY gonadal dysgenesis, highlighting the possibility that digenic inheritance may play a role in the large phenotypic spectrum associated with NR5A1 variants. We also identified two patients with multiple affected diagnostic DSD genes (Table 3). Patient 3 was found to harbor a previously reported p.Arg84His variant in NR5A1, alongside a rare variant in ZFPM2 (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in @GENE$ (@VARIANT$, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a single codon deletion at position 372 of NR5A1 (Table 3).",5765430,NR5A1;3638,SRD5A2;37292,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442,0
"Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (@VARIANT$), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants @VARIANT$ (p.Gly505Ser) in @GENE$ and c.353A > G (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,p.Leu593Phe;tmVar:p|SUB|L|593|F;HGVS:p.L593F;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the @GENE$ and @GENE$ proteins lead us to hypothesize that digenic variants in NRXN1 and NRXN2 contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; p.L16V) and USH2A (@VARIANT$).",3125325,CDH23;11142,USH1G;56113,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, DUOX2, @GENE$ and @GENE$).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a TPO mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and p.K618 were novel. @VARIANT$ is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and p.R528S and p.K618* are located in the cytoplasmic loops (Fig. S3C).",7248516,DUOXA2;57037,TPO;461,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,0
"Interestingly, we identified 5 patients (4.8%) with variants in @GENE$ (OPTN) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1.",4470809,optineurin;11085,TBK1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"(A) In addition to c.235delC in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of GJB3. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous p.A194T mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,DFNB1;2975,gap junction protein beta 3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"The c.1592G>A (@VARIANT$) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within @GENE$, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3).",6161649,SCUBE2;36383,SMAD1;21196,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Her mother with c.1339 + 3A>T in COL4A5 and her father with a missense mutation @VARIANT$ in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"Notably, not all @GENE$-@VARIANT$ carriers (II-3, II-6, III-4, III-5, III-7, IV-1, IV-3, IV-4 and obligate carriers II-4 and III-1) manifested the positive phenotypes (ER pattern in ECG or nocturnal SCD). This phenotypic incomplete penetrance might be modified by @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (@VARIANT$, p.G505D). A novel missense mutation was found in @GENE$ (c.398G>A, @VARIANT$).",6098846,TG;2430,DUOXA2;57037,c.1514G>A;tmVar:c|SUB|G|1514|A;HGVS:c.1514G>A;VariantGroup:10;CorrespondingGene:6528;RS#:867829370,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,1
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated @GENE$ mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, @VARIANT$; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"The @GENE$-@VARIANT$ variant is currently annotated as a mutation in the Human Gene Mutation Database (HGMD) database, having been identified in other LQTS subjects. KCNH2-p.K897T was previously associated with a prolonged QT interval in several different populations and can alter the biophysical properties of mutant channels (current density, activation, inactivation, and recovery from inactivation) and exacerbate the IKr reduction caused by other KCNH2 mutations. @GENE$-@VARIANT$ affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,0
"On the other hand, mis-localization of pendrin A372V from the plasma membrane is not restored by these treatments, suggesting these mutations may affect @GENE$ trafficking from the Golgi to the plasma membrane but not protein-folding. Here, we found that pendrin @VARIANT$, L445W, Q446R, and G672E did not bind to EphA2. Given the fact that loss of EphA2 disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of pendrin with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of pendrin from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with EphA2. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after @GENE$ stimulation.",7067772,pendrin;20132,ephrin-B2;3019,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(Ser872Gly) variant in PKD1, while only one fetus inherited the p.(@VARIANT$) PKD2 variant. The analysis of @GENE$ performed on the first fetus showed no mutations. We suggest that: 1) the PKD2 p.(Cys331Thr) variant is pathogenic, since it is de-novo in a patient with a renal cystic disease and is transmitted to both fetuses; 2) the p.(@VARIANT$) variant in PKD1 is hypomorphic, since it does not cause renal disease in the father (age 44 years), but worsens the renal phenotype when co-inherited with a @GENE$ mutation; 3) the missense variant p.(Arg872Gly) in PKD2, already described as disease-causing in HGMD database (Neumann et al.,), is likely benign, since it is present in a healthy man and does not segregate with disease in the fetuses.",7224062,PKHD1;16336,PKD2;20104,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,0
"Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, @GENE$, DUOXA2 and TPO).  A total of 6 TPO variants were separately found in 6 patients (6/43, 14%) in heterozygous status. All but 1 patient had a @GENE$ mutation in association with mutation(s) in different genes. A total of 2 novel variants, p.S309P and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and p.K618 were novel. @VARIANT$ is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and p.R528S and @VARIANT$ are located in the cytoplasmic loops (Fig. S3C).",7248516,DUOX2;9689,TPO;461,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,p.K618*;tmVar:p|SUB|K|618|*;HGVS:p.K618*;VariantGroup:4;CorrespondingGene:7253,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (@VARIANT$) and SLC26A4: c.1229C>A (@VARIANT$), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel FAT4 missense variant @VARIANT$).",5887939,DVL3;20928,CELSR2;1078,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In our study, we identified four genetic variants in three genes (@GENE$-p.R583H, KCNH2-@VARIANT$, @GENE$-p.K897T, and KCNE1-@VARIANT$).",5578023,KCNQ1;85014,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the @GENE$ gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0
"M3, @GENE$: p.(E173*). M4, @GENE$: @VARIANT$. M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"The proband in family PCG-139 also carried a rare @GENE$ variant (@VARIANT$) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for CYP1B1 and PITX2, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, @GENE$: @VARIANT$. M4, PITX2: p.(P179T).",6338360,PITX2;55454,CYP1B1;68035,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545,0
"We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, @VARIANT$, in one of the @VARIANT$ carriers (SH107-225) (Figure 4A). She inherited c.235delC of GJB2 from her father and did not have any known large genomic deletions within the @GENE$ locus (Figure 4B).",4998745,MITF;4892,DFNB1;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
"Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). The @VARIANT$ (p.His596Arg) mutation of @GENE$ has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). The c.317G>C (@VARIANT$) variant of PDGFRB, a rare single nucleotide polymorphism (SNP, rs544478083), has not yet been shown to be related to PFBC and is likely benign predicted by Mutation Taster, PolyPhen-2, and PROVEAN (data not shown).",8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2). While @GENE$ blocks VEGF/VEGFR2 signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,RASA1;2168,TIMP3;36322,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0
"This included the variants in @GENE$ (chr6, NM_000426.3:c.380A > G (@VARIANT$); MAF 1.76 x 10-5) and @GENE$ (chr10, NM_0002211:@VARIANT$ (p.Glu562del); MAF 3.871 x 10-5), which affected amino acid residues that were found to be highly conserved across species (Fig. 1).",8474709,LAMA2;37306,LOXL4;12977,p.Thr127Ala;tmVar:p|SUB|T|127|A;HGVS:p.T127A;VariantGroup:0;CorrespondingGene:3908,c.1684_1686del;tmVar:c|DEL|1684_1686|;HGVS:c.1684_1686del;VariantGroup:5;CorrespondingGene:84171,0
"To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and PITX2: c.535C>A, @VARIANT$) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and p.(H395N); PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,0
"Proband 17 inherited @GENE$ p. Trp1994Gly and CDON @VARIANT$ variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant.",8152424,CHD7;19067,FGFR1;69065,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"In families F and K, a heterozygous missense mutation of a @VARIANT$ of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB3;7338,GJB2;2975,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling.",6161649,ENG;92,SCUBE2;36383,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2). While @GENE$ blocks VEGF/VEGFR2 signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,TIMP3;36322,RASA1;2168,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"Three SNPs in SETX (rs1183768, rs543573, and @VARIANT$) were in perfect linkage disequilibrium and were considered to be one signal represented by rs2296871. We included only ALS subjects of European ancestry and compared to controls of European ancestry from ESP6500 and the 1000 Genomes Project. SPLINTER-predicted allele frequencies were used for common variants that were not confirmed by genotyping in ALS subjects. Using a Bonferonni-corrected significance level of 8.2x10-4, 3 variants were significantly more common in our ALS discovery cohort (rs3739927 and rs882709 in @GENE$, and @VARIANT$ in @GENE$).",4293318,SETX;41003,EWSR1;136069,rs2296871;tmVar:rs2296871;VariantGroup:39;CorrespondingGene:23064;RS#:2296871,rs41311143;tmVar:rs41311143;VariantGroup:21;CorrespondingGene:2130;RS#:41311143,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB3;7338,GJB6;4936,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with VAPB @VARIANT$ and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,SOD1;392,ANG;74385,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"We identified four genetic variants (@GENE$-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and @GENE$-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"This genetic synergism is also supported by the potential digenic inheritance of @GENE$ and @GENE$ mutations in Family 4. The proband, who had LRP6 p.(Asn1075Ser), p.(Ser127Thr), and WNT10A p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. The LRP6 p.(@VARIANT$) mutation substitutes highly-conserved asparagine with serine, which is predicted to destabilize the protein structure.",8621929,LRP6;1747,WNT10A;22525,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT5;71688,KCNH2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Three variants in three genes were rare, including the PROKR2 gene mutation [@VARIANT$], a novel heterozygous missense variant [c.1801G > A; p.(@VARIANT$)] in the @GENE$ gene (NM_001146029), as well as a splice site variation in the @GENE$ gene (NM_032242; MAF = 0.03 in GnomAD).",8446458,SEMA7A;2678,PLXNA1;56426,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of TEK to respond to ligand stimulation, indicating perturbed @GENE$ signaling.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, @VARIANT$), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a). The c.1787A>G (p.His596Arg) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019). The c.317G>C (@VARIANT$) variant of PDGFRB, a rare single nucleotide polymorphism (SNP, rs544478083), has not yet been shown to be related to PFBC and is likely benign predicted by Mutation Taster, PolyPhen-2, and PROVEAN (data not shown).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"a, b Immunoprecipitation of EphA2 with mutated @GENE$. myc-pendrin A372V, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of @GENE$ with mutated pendrin. Immunocomplex of myc-pendrin @VARIANT$, S166N and @VARIANT$ was not affected.",7067772,pendrin;20132,EphA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,SPTBN4;11879,MYOD1;7857,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and PITX2: @VARIANT$, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and @VARIANT$; PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"For example, two variants in proband P15, @VARIANT$ in @GENE$ and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother.",8152424,PROKR2;16368,DMXL2;41022,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,1
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, @VARIANT$, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,c.379T>A;tmVar:c|SUB|T|379|A;HGVS:c.379T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Three variants in three genes were rare, including the PROKR2 gene mutation [p.(Lys205del)], a novel heterozygous missense variant [@VARIANT$; p.(Glu436Lys)] in the SEMA7A gene (NM_001146029), as well as a splice site variation in the PLXNA1 gene (NM_032242; MAF = 0.03 in GnomAD). The SEMA7A gene variant was predicted as a VUS according to Varsome, whereas the PLXNA1 gene variation was classified as benign. The SEMA7A variant [@VARIANT$] was absent in the 92 exomes of our local database (Supplementary Table 8). The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving @GENE$, @GENE$, DCC, PROP1, PLXNA1, and SEMA7A genes (Table 3 and Supplementary Table 9).",8446458,DUSP6;55621,ANOS1;55445,c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750,p.(Glu436Lys);tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and @GENE$ @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ @VARIANT$ and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
Most had @GENE$ repeat expansion combined with another mutation (e.g. @GENE$ @VARIANT$ or TARDBP @VARIANT$; Supplementary Table 6).,5445258,C9orf72;10137,VCP;5168,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,A321V;tmVar:p|SUB|A|321|V;HGVS:p.A321V;VariantGroup:27;CorrespondingGene:23435,0
"Further molecular studies are needed to prove the deleterious character of the @GENE$ Lys205del variant. Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the @GENE$ gene variant [p.(@VARIANT$)].",8446458,PROKR2;16368,DUSP6;55621,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"Both the aborted foetuses carried the compound heterozygous pathogenic variants, namely PKD1: c.1386-2A > G and @GENE$: c.7583A > G (p.Y2528C) from each parent, and these variants were inferred to have contributed to the foetal PKD. 33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the PKD1: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: c.1675C > T (p.R559W) and @GENE$: @VARIANT$ (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.7942G > A;tmVar:c|SUB|G|7942|A;HGVS:c.7942G>A;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,0
"Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (@GENE$ @VARIANT$).",8152424,FGFR1;69065,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and @GENE$ @VARIANT$ with SETX p.I2547T and SETX p.T14I).,4293318,VAPB;36163,TAF15;131088,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"On the other hand, EphA2 overexpression did not affect localization of @VARIANT$.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,UBQLN2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Of these patients, one carried one heterozygous @GENE$ variant, three harbored two or three heterozygous variants in DUOX2, and six carried oligogenic mutations, including five cases comprising DUOX2 mutations plus a heterozygous mutation in TG or @GENE$ and one case carrying a single heterozygous mutation each in DUOXA2, SLC26A4, and TG. With available parental DNA samples, identified variants carried by the five cases (patients 3, 5, 7, 15, and 19) were of either paternal or maternal origin, and none came from one single parent (Figure 3). DUOX2 mutation numbers and types carried by patients were not correlated with CH clinical phenotypes, including disease severity, neuropsychological development, or prognosis. For example, patients 14 and 19 each carried one known truncating mutation (IVS28+1G>T) and a known inactivating mutation (p.R110Q or @VARIANT$). One showed severe CH and low intelligence level, and the other showed mild CH and normal intelligence. Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (@VARIANT$ or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism.",6098846,DUOX2;9689,DUOXA2;57037,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Her mother with @VARIANT$ in COL4A5 and her father with a missense mutation c.4421C > T in @GENE$ had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in COL4A4 genes.",6565573,COL4A4;20071,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"Other family members who have inherited TCF3 T168fsX191 and @GENE$/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of @GENE$ and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered @GENE$ without TES were found to be DFNB7/11, DFNB3, and @GENE$, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES.",4998745,DFNB1;2975,DFNB16;15401,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of USH2A (NM_007123), R5143C, @VARIANT$, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and Ankyrin 1 (@GENE$) identified in SH 94-208).",4998745,USH2A;66151,ANK1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,C4870F;tmVar:p|SUB|C|4870|F;HGVS:p.C4870F;VariantGroup:24;CorrespondingGene:7399,0
"In AS patient IID27, the two mutations in COL4A5 and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a).",6565573,COL4A4;20071,COL4A5;133559,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,TARDBP;7221,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; @VARIANT$); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, @VARIANT$, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for CDH23 , 11%-15% for PCDH15 , and for USH2A in USH2 patients, whereas the implication of VLGR1 and @GENE$ in the latter was minor.",3125325,USH2A;66151,WHRN;18739,c.494C>T;tmVar:c|SUB|C|494|T;HGVS:c.494C>T;VariantGroup:185;CorrespondingGene:4647;RS#:111033174;CA#:278676,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"The mutation @VARIANT$ is expected to abolish the hydrophobic interaction of G213 with adjacent residues. Sequences of orthologs and predicted 2D structure of human WNT10A protein. (A) The alignment of orthologs of the human WNT10A protein. The R171 and G213 residues are represented by arrowheads. (B) The predicted 2D structure of human @GENE$ protein. The R171 and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The @VARIANT$ residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. I312 is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of @GENE$ with its receptors.",3842385,WNT10A;22525,EDA;1896,G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,G257;tmVar:c|Allele|G|257;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882,0
"CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in @GENE$ were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and FGFR1 c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant @VARIANT$ of another PSIS gene, CDON, was also found in case @GENE$ who carried a missense variant in CHD7, a causative gene of IHH.",8152424,CCDC88C;18903,P17;9694,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and @GENE$ (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"In patient AVM226, we identified the compound heterozygous variants @VARIANT$ (p.Val1259Ile) and @VARIANT$ (p.Gln989Leu) in DSCAM (table 2). @GENE$ and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.",6161649,DSCAML1;79549,DSCAM;74393,c.3775G>A;tmVar:c|SUB|G|3775|A;HGVS:c.3775G>A;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,c.2966A>T;tmVar:c|SUB|A|2966|T;HGVS:c.2966A>T;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"These two individuals were heterozygous carriers of @VARIANT$ mutation in @GENE$ and @VARIANT$ in GGCX. Since heterozygous carriers of p.R1141X in ABCC6 alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance. In this case, haploinsufficiency of the carboxylase activity and reduced ABCC6 functions could be complementary or synergistic. The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the ABCC6 gene (p.R1141X) and the @GENE$ gene (p.S300F) yet did not display any cutaneous findings are not clear.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"This is in line with the data from previous studies; according to which, @GENE$ is a causative gene of ALS-FTD. The NEK1 @VARIANT$ variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with @GENE$ variants (L106V and @VARIANT$).",6707335,TBK1;22742,CCNF;1335,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,REEP4;11888,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,DCTN1;3011,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (@VARIANT$, @VARIANT$). A novel missense mutation was found in @GENE$ (c.398G>A, p.R133H).",6098846,TG;2430,DUOXA2;57037,c.1514G>A;tmVar:c|SUB|G|1514|A;HGVS:c.1514G>A;VariantGroup:10;CorrespondingGene:6528;RS#:867829370,p.G505D;tmVar:p|SUB|G|505|D;HGVS:p.G505D;VariantGroup:10;CorrespondingGene:7173;RS#:867829370,0
"During mesoderm development, the expression of MEOX1 is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.   CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified.",7549550,TBX6;3389,RIPPLY1;138181,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Three variants in three genes were rare, including the PROKR2 gene mutation [p.(Lys205del)], a novel heterozygous missense variant [@VARIANT$; p.(Glu436Lys)] in the SEMA7A gene (NM_001146029), as well as a splice site variation in the PLXNA1 gene (NM_032242; MAF = 0.03 in GnomAD). The SEMA7A gene variant was predicted as a VUS according to Varsome, whereas the @GENE$ gene variation was classified as benign. The SEMA7A variant [p.(Glu436Lys)] was absent in the 92 exomes of our local database (Supplementary Table 8). The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, ANOS1, DCC, PROP1, PLXNA1, and @GENE$ genes (Table 3 and Supplementary Table 9). On the other hand, no disease-causing digenic combinations included the PROKR2 gene variant p.(Lys205del). The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations.",8446458,PLXNA1;56426,SEMA7A;2678,c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (c.1514G>A, p.G505D). A novel missense mutation was found in DUOXA2 (c.398G>A, @VARIANT$). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, p.H678R and @VARIANT$, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001).",6098846,TG;2430,DUOX2;9689,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,p.S1067L;tmVar:p|SUB|S|1067|L;HGVS:p.S1067L;VariantGroup:4;CorrespondingGene:50506;RS#:269868;CA#:7537960,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB3;7338,GJB2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"On the other hand, EphA2 overexpression did not affect localization of @VARIANT$.    The substitutions of Leu117 to Phe (L117F), @VARIANT$ (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA.",7067772,pendrin;20132,EPHA2;20929,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,Ser166 to Asn;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"   The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that @GENE$ could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and @GENE$ mutations.",7067772,EphA2;20929,SLC26A4;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,VPS13C;41188,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Two previous mouse studies have reported homozygous PKHD1 variants in addition to either a monoallelic @GENE$ or @GENE$ variant resulting in severe phenotypes and embryonic lethality. 45 ,  46  Therefore, we hypothesized that the combinational effects of the ADPKD and ARPKD traits having been proposed to produce further severe and early-onset phenotypes. The genetic experiment results in the present study provided probable evidence in favour of phenotypic amplification in the digenic patient. Follow-up functional experiments are needed to elucidate the pathogenic mechanism of this case.       Family 24 and Family 25 were screened out using prenatal imaging diagnosis for foetal PKD, although additional syndromic manifestations appeared in Family 25. The genetic diagnosis for both these families was MKS consistent with autosomal recessive (AR) patterns. Biallelic pathogenic variants in the TMEM67 gene may lead to MKS3, with overlapping symptoms to ADPKD, including renal cysts and central nervous dysplasia, among which the latter was not evidently manifested in Family 24. One possible explanation for this could be that @VARIANT$ (@VARIANT$) was possibly a hypomorphic variant.",8256360,PKD1;250,PKD2;20104,c.637C > T;tmVar:c|SUB|C|637|T;HGVS:c.637C>T;VariantGroup:3;CorrespondingGene:5314;RS#:866575098;CA#:138924774,p.R213C;tmVar:p|SUB|R|213|C;HGVS:p.R213C;VariantGroup:3;CorrespondingGene:91147;RS#:866575098,0
"Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Sequence alterations were detected in the COL6A3 (rs144651558), RYR1 (@VARIANT$), @GENE$ (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,CAPN3;52,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"For example, patients 14 and 19 each carried one known truncating mutation (@VARIANT$) and a known inactivating mutation (@VARIANT$ or p.R885Q). One showed severe CH and low intelligence level, and the other showed mild CH and normal intelligence. Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (p.R110Q or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including @GENE$, @GENE$, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TPO;461,TG;2430,IVS28+1G>T;tmVar:c|SUB|G|IVS28+1|T;HGVS:c.IVS28+1G>T;VariantGroup:33;CorrespondingGene:50506,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Pathogenic effects of @GENE$ @VARIANT$ and NDUFS8 I126V variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the @GENE$ @VARIANT$ variant in MH.",6072915,GBE1;129,RYR1;68069,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,p.T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-@GENE$ @VARIANT$ to immunoprecipitate HA-@GENE$ E103D and HA-TEK @VARIANT$, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant p.A2282T and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The @GENE$ missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between p.R2003H FLNB and @VARIANT$ OFD1 (figure 3D).",7279190,TTC26;11786,FLNB;37480,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene. Variants in the DYNC1H1 gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the DYNC1H1 gene in fALS and sALS patients, suggesting its role in ALS. Based on our findings, we strengthen the potential link between @GENE$ variants and ALS.     Given that there are genetic and symptomatic overlaps among many neurodegenerative diseases, it has been suggested that causative variants might play roles in multiple disorders. Two heterozygous variants (H398R and @VARIANT$) were detected in the GBE1 gene.",6707335,MATR3;7830,DYNC1H1;1053,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,R166C;tmVar:p|SUB|R|166|C;HGVS:p.R166C;VariantGroup:21;CorrespondingGene:2632;RS#:376546162;CA#:2499951,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,ENG;92,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel @GENE$ missense variant @VARIANT$).",5887939,FZD1;20750,FAT4;14377,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"          Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the GGCX and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a @VARIANT$ (p.V255M) of the @GENE$ enzyme was detected (Fig. 3b).",2900916,VKORC1;11416,gamma-glutamyl carboxylase;639,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,valine by methionine at position 255;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ p.R148Q, PTK7 @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (c.1823-1G>C), inherited digenically with a homozygous @GENE$ nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1;68136,DUOX2;9689,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,1
"R85C in @GENE$ (MIM 607123; NM_144773.2; @VARIANT$) inherited from an unaffected mother and c.1306A>G;@VARIANT$ in @GENE$ (MIM 606417; NM_018117.11; rs34602786) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1).",5505202,PROKR2;16368,WDR11;41229,rs141090506;tmVar:rs141090506;VariantGroup:1;CorrespondingGene:128674;RS#:141090506,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"We identified four genetic variants (@GENE$-p.R583H, @GENE$-p.C108Y, KCNH2-p.K897T, and KCNE1-@VARIANT$) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNQ1;85014,KCNH2;201,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$).",5887939,CELSR1;7665,SCRIB;44228,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, @VARIANT$, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,c.379T>A;tmVar:c|SUB|T|379|A;HGVS:c.379T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and @GENE$ (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,SPTBN4;11879,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,0
"(A) Patient with homozygous variants in both @GENE$ and @GENE$ genes. NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and c.850C>T (@VARIANT$) in ANO5 and SGCA genes, respectively.",6292381,ANO5;100071,SGCA;9,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,R284C;tmVar:p|SUB|R|284|C;HGVS:p.R284C;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,1
"21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  @GENE$, 23  @GENE$, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, @VARIANT$) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,EBNA1BP2;4969,TRIP6;37757,p.Asn2604Lys;tmVar:p|SUB|N|2604|K;HGVS:p.N2604K;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"          Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of @GENE$ are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, @VARIANT$, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of @GENE$ with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected.",7067772,pendrin;20132,EphA2;20929,Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,alsin;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
GFP-@GENE$ R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2).,5953556,CYP1B1;68035,TEK;397,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of @GENE$ (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and @VARIANT$ (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin F355L mutations on EphA2 interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,Phe335 to Leu;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"  Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (@VARIANT$); P1, P2: thyrotropin >100 microU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (@VARIANT$) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred. Conclusion: This is a report of digenic mutations in DUOX1 and DUOX2 in association with CH, and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype. Our studies provide evidence for a digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically ascertained CH. Whole-exome sequencing in siblings with a known homozygous @GENE$ mutation and unusually marked congenital hypothyroidism (CH) identified the human homozygous @GENE$ mutation, segregating with CH.",5587079,DUOX2;9689,DUOX1;68136,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,1
"This hypothesis was further supported when a patient with Kallmann syndrome was discovered to carry the same PROKR2 heterozygous mutation as our proband, @VARIANT$, in combination with a second heterozygous mutation in FGFR1, @VARIANT$;p.A604T (NM_023110.2), thereby providing evidence for a digenic basis for the syndrome. @GENE$ and @GENE$ are both expressed in the hypothalamus and pituitary, and reduced expression or activity of PROKR2 is implicated in both Kallmann syndrome and PSIS, perhaps because of the important role this signaling pathway plays in endocrine angiogenesis and neuronal migration in this region of the central nervous system.",5505202,Prokineticin 2;9268,PROKR2;16368,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1810G>A;tmVar:c|SUB|G|1810|A;HGVS:c.1810G>A;VariantGroup:5;CorrespondingGene:2260;RS#:1412996644,0
"    A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Furthermore, @GENE$ presented 2 variants in patient 1. Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in  Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via @GENE$ 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1.",6726737,RIPK4;10772,NOTCH1/2;4851;4853,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys).",8152424,PROKR2;16368,DDB1 and CUL4 associated factor 17;80067;1642,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different @GENE$ mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,TIA1;20692,SQSTM1;31202,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, @VARIANT$; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,p.Ser817Cys;tmVar:p|SUB|S|817|C;HGVS:p.S817C;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"A novel variant @GENE$ @VARIANT$ (p.K618R) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 @VARIANT$, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (@GENE$ p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,SCRIB;44228,CELSR1;7665,c.1853A > G;tmVar:c|SUB|A|1853|G;HGVS:c.1853A>G;VariantGroup:2;CorrespondingGene:5754;RS#:139041676;CA#:3816321,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB6;4936,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Our USH1 patient (Case #4) had segregated MYO7A:@VARIANT$ and PCDH15:c.158-1G>A. Molecular analyses in mouse models have shown many interactions among the USH1 proteins. In particular, MYO7A directly binds to PCDH15 and both proteins are expressed in an overlapping pattern in hair bundles in a mouse model. PCDH15:c.158-1G>A, predicted to alter the splice donor site of intron 3, has been classified as pathogenic. @GENE$:p.Ala771Ser is a non-truncating mutation, but was previously reported as disease-causing. So, we consider the patient to be the first reported case of MYO7A/@GENE$ digenic inheritance.     However, we should be aware of two limitations of MPS technology. First, the target region of MPS cannot cover all coding exons of USH genes. Actually, the coverage of the target exons was 97.0% in our study. So, it is impossible to detect a mutation in a region which is not covered using this system (Case #9: @VARIANT$).",3949687,MYO7A;219,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.5821-2A>G;tmVar:c|SUB|A|5821-2|G;HGVS:c.5821-2A>G;VariantGroup:42;CorrespondingGene:64072,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (@VARIANT$).",3125325,USH2A;66151,CDH23;11142,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"A single @GENE$ mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Additionally, a novel variant (@VARIANT$) in the 5' untranslated region of the @GENE$ gene was also detected. As the screening of untranslated regions was not in the scope of our research, we did not examine it further.   No SOD1 and TARDBP gene variants were found in this cohort. We would like to point out that 37 of the analyzed samples were overlapping samples from a previous study and were known to be negative for SOD1 and TARDBP mutations. Still, based on earlier results, one would expect to detect SOD1 variants in the further 70 samples. Variants Detected in Minor ALS Genes By focusing on the analysis of minor ALS genes, 33 variants (31 missense and 2 splicing) were detected in 26 genes corresponding to 29 patients (27.1% of all patients,  Supplementary Table 2 ). No patients were identified as being homozygous for any of the detected variants. A patient was carrying two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene; both variants localized in the motor domain of the protein.",6707335,FUS;2521,DYNC1H1;1053,c.-25C > T;tmVar:c|SUB|C|-25|T;HGVS:c.-25C>T;VariantGroup:38;CorrespondingGene:2521,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"(A) Segregation of the @GENE$-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and @GENE$-@VARIANT$ variants in the long-QT syndrome (LQTS) family members.",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (@VARIANT$; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in S100A13. Mutation name is based on the full-length @GENE$ (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"Moreover, patients carrying a @GENE$ Pro943Leu mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (@VARIANT$) and MYBPC3 (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and TNNT2 (Asn83His), both sarcomeric genes. Here we reported heterozygous variants in genes that play roles in two different cardiomyocyte components; MYH7:part of the sarcomere, and LAMA4:part of the ECM/signalling component. To our knowledge, this is the first description of digenic mutations in @GENE$ and LAMA4.",6359299,LAMA4;37604,MYH7;68044,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0
"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, @VARIANT$), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,rs2302686;tmVar:rs2302686;VariantGroup:2;CorrespondingGene:4040;RS#:2302686,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,HS1BP3;10980,MRPL15;32210,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"In this family, the patient (II: 1) with digenic heterozygous mutations of KCNH2 @VARIANT$ and @GENE$ @VARIANT$ presented the earliest phenotype of LQTS, and she suffered from syncope, torsades de pointes, and ventricular fibrillation more frequently at rest, whereas the members (I:1 and II:2) without KCNH2 p.307_308del showed normal QT intervals and cardiac function. The changed site of KCNH2 p.307_308 was highly conserved across most species, suggesting p.307_308 of @GENE$ protein playing a significant role in function.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and @GENE$ (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in @GENE$, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,TANK-binding kinase 1;22742,OPTN;11085,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG @VARIANT$, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"Of note, the same variant @VARIANT$ was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (@GENE$). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)p. Gln91Arg, and FGFR1 c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant p. Val969Ile of another PSIS gene, @GENE$, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. CDON seems to act similarly as CCDC88C through a digenic/oligogenic model to contribute to IHH. Case P06 had a missense variant in GADL1 (@VARIANT$), predicted as probably damaging.",8152424,TACR3;824,CDON;22996,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Ser221Cys;tmVar:p|SUB|S|221|C;HGVS:p.S221C;VariantGroup:5;CorrespondingGene:339896;RS#:775162663;CA#:2294666,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both PKD1 and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly).",7224062,PKD2;20104,PKD1;250,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,FZD6;2617,FZD1;20750,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 @GENE$, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by OGG1. 20  The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,CUX1;22551,TRIP6;37757,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,0
"No significant change was observed with HA-@GENE$ G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type @GENE$ and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK. The residues E103, I148, and @VARIANT$ lie in the N-terminal extracellular domain of TEK (Fig. 1d).",5953556,TEK;397,CYP1B1;68035,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,Q214;tmVar:p|Allele|Q|214;VariantGroup:10;CorrespondingGene:7010,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"ShScb, ADD3 or @GENE$ depleted podocytes were obtained by transduction with the respective shRNAs lentiviral particles and subsequent puromycin selection.   Human ADD3 and KAT2B, were subcloned from human full-length cDNA (ADD3: clone IMAGE: 6649991; KAT2B clone IMAGE: 30333414) into the expression vectors pLentiGIII and PLEX-MCS, respectively. An HA tag was added in frame, before the stop codon, to the C terminus of ADD3 and KAT2B. The @GENE$ @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol.",5973622,KAT2B;20834,ADD3;40893,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0
"Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-@VARIANT$, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (c.229C>T; @VARIANT$) and d) the @VARIANT$ (p.I80Gfs*13) in @GENE$. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1
"Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,1
"We previously reported two Probands harboring a homozygous, known pathogenic nonsense mutation in @GENE$ (@VARIANT$), both of whom exhibited uncharacteristically severe CH. Whole-exome sequencing in this kindred detected digenicity for a homozygous essential splice site @GENE$ mutation (@VARIANT$) in affected individuals, found to be pathogenic in vitro and likely contributing to the phenotypic severity.",5587079,DUOX2;9689,DUOX1;68136,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,1
"A rare variant in @GENE$, c.428C>T; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/FOG2 (c.1632G>A; p.Met544Ile) pathogenic missense alteration was identified. No additional variants in other genes associated with testicular development and DSD were identified by our panel in Cases 3, 5 and 6. We were not able to further analyze Case 4 because of a lack of sample availability. 2.3. Transcription Activity and Protein Expression Testing of Novel NR5A1 Variants To study the impact of the three novel missense variants of @GENE$ on transactivation activity of regulated genes, HEK293 cells were co-transfected with WT or mutant NR5A1 expression vectors and three different promoter reporter constructs essential for steroid and sex hormone biosynthesis. All three novel NR5A1 variants had significantly reduced activity on the CYP17A1 reporter compared to WT (Figure 2A). These results were confirmed for the @VARIANT$ and @VARIANT$ variants when using the reporters for CYP11A1 and HSD17B3 (Figure 2B,C).",7696449,AMH;68060,NR5A1;3638,His24Leu;tmVar:p|SUB|H|24|L;HGVS:p.H24L;VariantGroup:4;CorrespondingGene:6736;RS#:1262320780,Cys30Ser;tmVar:p|SUB|C|30|S;HGVS:p.C30S;VariantGroup:5;CorrespondingGene:6662;RS#:1003847603;CA#:293780979,0
"In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD.",6707335,GRN;1577,SQSTM1;31202,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"The @VARIANT$ (p.Cys531Tyr) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3).",6161649,SCUBE2;36383,MAP4K4;7442,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (@GENE$ c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD1;20750,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,0
"Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (@VARIANT$), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (@VARIANT$).",5887939,PRICKLE4;22752,CELSR2;1078,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0
"The c.229C>T (@VARIANT$) variant in S100A3 and c.238-241delATTG (@VARIANT$) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2.             Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, S100A13 and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.",6637284,S100A13;7523,S100A3;2223,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"    Sanger sequencing Sanger sequencing was performed on available samples for confirmation of @GENE$ and @GENE$ variants in family members to perform segregation analysis. Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (@VARIANT$/c.1145A > G) and MYO6 (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the 497A>G (@VARIANT$) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of @GENE$ and @GENE$ in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against Cx26 (a) and Cx31 (b).,2737700,Cx31;7338,Cx26;2975,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Cys238Arg variant lost transcriptional activity on the CYP17 promoter reporter, while @VARIANT$ and @VARIANT$ behaved similar to wild type. These results were in line with bioinformatics simulation studies. Additional DSD variations, in the @GENE$ and @GENE$ genes, respectively, were identified in the two 46,XY individuals without CHD.",5893726,LRP4;17964,LHCGR;37276,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0
"However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, @GENE$ (IGSF10) @VARIANT$, and the rest were missense variants.",8152424,CCDC88C;18903,immunoglobulin superfamily member 10;18712,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,0
"    A new pathogenic variant in @GENE$ affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, @VARIANT$, was identified in patient #3.",6567512,BBS2;12122,BBS7;12395,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"Circles, female; squares, male; gray, TNFRSF13B/TACI @VARIANT$ mutation; blue @GENE$ @VARIANT$ mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/@GENE$ C104R mutations.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"We observed that recombinant @GENE$ and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of TEK (@VARIANT$)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (@VARIANT$) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"One missense mutation (p.Q1916R) was found in the major subunit of the L-type calcium channel gene @GENE$ by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female CACNA1C-@VARIANT$ mutation carriers, which led to the incomplete penetrance.",5426766,CACNA1C;55484,SCN5A;22738,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely @VARIANT$, p.P79T, p.S82T, p. A85P, p.L86F, p.F112S, @VARIANT$, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.Q70Hfs*8;tmVar:p|FS|Q|70|H|8;HGVS:p.Q70HfsX8;VariantGroup:8;CorrespondingGene:6012,p.R127L;tmVar:p|SUB|R|127|L;HGVS:p.R127L;VariantGroup:19;CorrespondingGene:2296;RS#:1085307884,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"(b) The changed site of @GENE$ gene (position 1864) increased the corresponding amino acid residues and nearby sequences hydrophobicity, but the influence was not significant DISCUSSION In our study, the proband with overlapped phenotypes of young early-onset LQTS and sinoatrial node dysfunction was first demonstrated to carry with the digenic heterozygous and pathogenic mutations of @GENE$ @VARIANT$ and SCN5A @VARIANT$. KCNH2 p.307_308del induced a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized, which thus mainly caused LQTS.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Three variants in three genes were rare, including the @GENE$ gene mutation [@VARIANT$], a novel heterozygous missense variant [@VARIANT$; p.(Glu436Lys)] in the SEMA7A gene (NM_001146029), as well as a splice site variation in the @GENE$ gene (NM_032242; MAF = 0.03 in GnomAD).",8446458,PROKR2;16368,PLXNA1;56426,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750,0
"Moderate iodine deficiency in association with double heterozygosity for @GENE$ and @GENE$ mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (c.1823-1G>C), inherited digenically with a homozygous DUOX2 nonsense mutation (@VARIANT$, p. R434*). The tertiary structure of DUOX1 and -2 is summarized in ; aberrant splicing of DUOX1 (@VARIANT$) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1;68136,DUOX2;9689,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (@VARIANT$; p.L16V) and @GENE$ (c.9921T>G).",3125325,MYO7A;219,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"In our study, we identified four genetic variants in three genes (KCNQ1-p.R583H, @GENE$-p.C108Y, KCNH2-@VARIANT$, and @GENE$-@VARIANT$).",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Immunocomplex of myc-@GENE$ @VARIANT$, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of @GENE$ and mutated pendrin triggered by ephrin-B2 stimulation.",7067772,pendrin;20132,EphA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"@VARIANT$ might affect the normal splicing of exons in the PROK2 gene, and the novel variant c.306G > C (@VARIANT$) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a PROK2 gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the @GENE$ gene were found in eight patients. c.337 T > C (p. Tyr113His) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. c.491G > A (p. Arg164Gln) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors. The hot spot variant c.533G > C (p. Trp178Ser) was found in six patients and located in the transmembrane domain of the protein, which could significantly reduce the release of ionized calcium and the signal activity.                             The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the FGF/@GENE$ signalling pathway.",8796337,PROKR2;16368,FGFR1;69065,c.223 - 4C > A;tmVar:c|SUB|C|223-4|A;HGVS:c.223-4C>A;VariantGroup:21;CorrespondingGene:60675,p. Arg102Ser;tmVar:p|SUB|R|102|S;HGVS:p.R102S;VariantGroup:20;CorrespondingGene:3730,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,SPG11;41614,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"The @VARIANT$ frameshifting mutation, and the @VARIANT$ and p.R66W missense mutations result in the absence of a secreted protein. (B) Upper panels: Representative western blots for the phosphorylated and total forms of @GENE$ (left panel) and @GENE$ (right panel) in GN11 cells following a 20 min incubation with serum-free medium (mock, negative control), 100 ng/ml of purified recombinant human Sema3A, or the conditioned media from transfected COS-7 cells producing wild-type or mutated Sema3A proteins.",3426548,FAK;7314,ERK1/2;5595;5594,p.D538fsX31;tmVar:p|FS|D|538||31;HGVS:p.D538fsX31;VariantGroup:12;CorrespondingGene:2260,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,1
"In families F and K, a heterozygous missense mutation of a @VARIANT$ of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for @GENE$/235delC (Fig. 1g, i) and GJB2/@VARIANT$ (Fig. 1l, n), respectively.",2737700,GJB3;7338,GJB2;2975,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,0
"DSCAML1 and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2).",6161649,DSCAM;74393,PTPN13;7909,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"These phenotypes were specific, since coinjection of nonmutant human @GENE$ or OTUD4 mRNA rescued all phenotypes (Fig. 3, and Fig. S4 in the Supplementary Appendix). RNF216 mRNA encoding @VARIANT$ and @GENE$ mRNA encoding @VARIANT$ were less effective in rescuing the phenotypes induced by double-MO injection (Fig. 3, and Fig. S4 in the Supplementary Appendix), suggesting not only that these mutant alleles encode functionally deficient proteins but also that epistatic interactions between these mutations contribute to the disease phenotype in the index pedigree.",3738065,RNF216;19442,OTUD4;35370,R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853,G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"We report digenic variants in SCRIB and @GENE$ associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,CELSR1;7665,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"This genetic synergism is also supported by the potential digenic inheritance of @GENE$ and WNT10A mutations in Family 4. The proband, who had LRP6 p.(@VARIANT$), p.(Ser127Thr), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Four genes (including AGXT2, @GENE$, SCAP, @GENE$) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,ZFHX3;21366,TCF4;2407,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in @GENE$     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"Given the reported normal function of pendrin L117F and pendrin @VARIANT$ as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of @GENE$ mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 p.P642R, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"          In a second example, we identified a monoallelic change in SRD5A2 (c.G680A, @VARIANT$, rs9332964:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of @GENE$, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014).",5765430,SF1;138518,SRD5A2;37292,p.Arg227Gln;tmVar:p|SUB|R|227|Q;HGVS:p.R227Q;VariantGroup:0;CorrespondingGene:6716;RS#:543895681,single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Since heterozygous carriers of @VARIANT$ in ABCC6 alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance. In this case, haploinsufficiency of the carboxylase activity and reduced ABCC6 functions could be complementary or synergistic. The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (p.R1141X) and the @GENE$ gene (@VARIANT$) yet did not display any cutaneous findings are not clear.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, p. A85P, p.L86F, p.F112S, @VARIANT$, p.G149D, and @VARIANT$, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.R127L;tmVar:p|SUB|R|127|L;HGVS:p.R127L;VariantGroup:19;CorrespondingGene:2296;RS#:1085307884,p.R170W;tmVar:p|SUB|R|170|W;HGVS:p.R170W;VariantGroup:59;CorrespondingGene:1805,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a).",8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, DVL3 p.R148Q, @GENE$ @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Somatic overgrowth associated with homozygous mutations in both @GENE$ and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ c.1200G>C (@VARIANT$) and MAN1B1 @VARIANT$ (p.R334C), associated with congenital birth defects in two patients from a consanguineous family.",4853519,MAN1B1;5230,SEC23A;4642,p.M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Among others, a known missense variant was detected in the @GENE$ gene (@VARIANT$), which is associated with mitochondrial disorders and Charcot-Marie-Tooth disease, and two variants of conflicting significance in the @GENE$ gene (H398R and @VARIANT$), which is associated with autosomal recessive adult-type polyglucosan body disease (Online Mendelian Inheritance in Man).",6707335,GJB1;137,GBE1;129,R230C;tmVar:p|SUB|R|230|C;HGVS:p.R230C;VariantGroup:28;CorrespondingGene:2705;RS#:587781246;CA#:270921,R166C;tmVar:p|SUB|R|166|C;HGVS:p.R166C;VariantGroup:21;CorrespondingGene:2632;RS#:376546162;CA#:2499951,0
"These results suggest that the proband's oligodontia likely resulted from these synergistic mutations in @GENE$ and WNT10A.       3.5. Predicted Structural Alterations and Pathogenicity of LRP6 Missense Mutations Computational prediction of the structural impact for the five LRP6 missense mutations on protein stability demonstrated that p.Met168Arg, p.Ala754Pro, and p.Asn1075Ser were destabilizing mutations with DeltaDeltaG values of 2.19, 1.39, and 0.96, respectively. Particularly, p.Met168Arg and @VARIANT$ were highly destabilizing, as their DeltaDeltaGs were higher than 1.00 kcal mol-1. In contrast, the other two missense variants, p.Ser817Cys and @VARIANT$, were predicted to stabilize the protein, having DeltaDeltaG values of -0.6 and -0.3. Amino acid sequence alignment and analysis for ortholog proteins of LRP6 and LRP5 were also performed to evaluate the phylogenetic conservation of specific amino acids at the five mutated positions. Methionine168 of human LRP6 was completely conserved in all of the LRP6 and @GENE$ ortholog protein sequences we scrutinized (Figure 5A).",8621929,LRP6;1747,LRP5;1746,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ c.109C>T. (b) Electropherograms of unaffected family member (II-2) and subject with BSP+ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of @VARIANT$ among vertebrates                @GENE$ missense variant A TOR2A nonsynonymous SNV (@VARIANT$ [NM_130459.3], p.Arg190Cys [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,REEP4;11888,TOR2A;25260,Arg37;tmVar:p|Allele|R|37;VariantGroup:10;CorrespondingGene:80346;RS#:780399718,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Sequence alterations were detected in the @GENE$ (rs144651558), @GENE$ (@VARIANT$), CAPN3 (@VARIANT$), and DES (rs144901249) genes.",6180278,COL6A3;37917,RYR1;68069,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"These results were confirmed for the @VARIANT$ and @VARIANT$ variants when using the reporters for @GENE$ and @GENE$ (Figure 2B,C).",7696449,CYP11A1;37347,HSD17B3;20089,His24Leu;tmVar:p|SUB|H|24|L;HGVS:p.H24L;VariantGroup:4;CorrespondingGene:6736;RS#:1262320780,Cys30Ser;tmVar:p|SUB|C|30|S;HGVS:p.C30S;VariantGroup:5;CorrespondingGene:6662;RS#:1003847603;CA#:293780979,0
"However, it was hard to determine whether the coexisting interactions of KCNH2 p.307_308del and SCN5A @VARIANT$ increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while @GENE$ mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 @VARIANT$ and SCN5A p.R1865H by WES and predisposing genes analyses.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The @GENE$ gene [c.340G > T; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the SEMA7A variant [@VARIANT$; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,DUSP6;55621,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.1759G > A;tmVar:c|SUB|G|1759|A;HGVS:c.1759G>A;VariantGroup:7;CorrespondingGene:8482,0
"No mutations in @GENE$, TPO, or @GENE$ gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: @VARIANT$ (p.M927V) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,SLC5A5;37311,IYD;12352,c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the @GENE$ gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,KCNE2;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,CAPN11;21392,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (@VARIANT$, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,g.68531T>G;tmVar:g|SUB|T|68531|G;HGVS:g.68531T>G;VariantGroup:11;CorrespondingGene:4040,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Notably, not all @GENE$-Q1916R carriers (II-3, II-6, III-4, III-5, III-7, IV-1, IV-3, IV-4 and obligate carriers II-4 and III-1) manifested the positive phenotypes (ER pattern in ECG or nocturnal SCD). This phenotypic incomplete penetrance might be modified by @GENE$-@VARIANT$ variant and sex. As shown in Table 3, all male individuals carrying the CACNA1C-@VARIANT$ mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant SCN5A-R1193Q showed the ERS phenotypes.",5426766,CACNA1C;55484,SCN5A;22738,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"Our data are consistent with those of Rafiq et al. and Rymen et al., as we found reduced @GENE$ protein levels and glycosylation defects in patients double homozygous for the @VARIANT$ MAN1B1 and the @VARIANT$ @GENE$ mutations.",4853519,MAN1B1;5230,SEC23A;4642,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,12000 G>C;tmVar:g|SUB|G|12000|C;HGVS:g.12000G>C;VariantGroup:14;CorrespondingGene:10484,0
"We observed that recombinant TEK and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of @GENE$ (p.E103D)::CYP1B1 (p.A115P), TEK (@VARIANT$)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (@VARIANT$) exhibit perturbed interaction.",5953556,CYP1B1;68035,TEK;397,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, @VARIANT$, p.Tyr27His), MBD5 (NM_018328.4, c.2000T>G, @VARIANT$), and @GENE$ (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0
"The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the SLC20A2 mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Three independent bioinformatics algorithms, SIFT, PolyPhen-2, and MutationTaster predicted both the 284G>A MUM1L1 and the 2701C>T @GENE$ mutations as benign, suggesting that mutations in these genes are unlikely to be responsible for abnormalities found in our affected patients. The 790A>G @GENE$ mutation was predicted to be benign by SIFT, possibly damaging by PolyPhen-2 (P = 0.463), and damaging by MutationTaster (P = 0.999). Sash3 is preferentially expressed in lymphoid tissues, and mutation of this gene in mouse indicates that it is required for generation of adaptive immune responses. Furthermore, although mice with mutation in Sash3 have smaller lymphoid organs, reduced T-cell proliferation and cytokine production, and reduction of marginal zone B cells, they are morphologically normal. Therefore, we assume that mutation in this gene cannot explain phenotypic abnormalities in the affected patients. Both the @VARIANT$ mutation in SEC23A and the @VARIANT$ mutation in MAN1B1 were within highly conserved residues and were predicted to be damaging by all three different bioinformatics algorithms (P = 0.999) (Supplemental Figs. S1and S2).",4853519,NUP214;38008,SASH3;10362,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of @GENE$ (NM_007123), @VARIANT$, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and @GENE$ (ANK1) identified in SH 94-208).",4998745,USH2A;66151,Ankyrin 1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,R5143C;tmVar:p|SUB|R|5143|C;HGVS:p.R5143C;VariantGroup:6;CorrespondingGene:7399;RS#:145771342;CA#:182576,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"We identified four genetic variants (@GENE$-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas @GENE$-@VARIANT$, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,Cx31;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"The ADD3 @VARIANT$ and KAT2B @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol. All constructs were verified by sequencing. ADD3 or KAT2B depleted podocytes were transduced with WT or mutant @GENE$ or @GENE$ lentiviral particles, respectively.",5973622,ADD3;40893,KAT2B;20834,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0
"There is thus strong support from human, murine and equine studies for the pathogenicity of the @GENE$ @VARIANT$ mutation in our family. Our study also offers new insights into the role of TNFRSF13B/TACI mutations in the pathogenesis of CVID. The C104R mutant is a low frequency variant in population databases (0.32% in Exome Aggregation Consortium) and although earlier publications considered this variant to be disease-causing and expressed in up to 10% of CVID patient cohorts, it, and other TNFRSF13B/@GENE$ variants were subsequently found to be present in ~2% of healthy control populations. Although functional studies of C104R mutant alleles have demonstrable defects in B-cell development, switching and differentiation, it is considered a risk allele for CVID, with a relative risk of 4.2 and it has long been speculated that second mutations may be identified in these families. This study is the first demonstration of such digenic inheritance in a CVID-like disorder. In this family, the TNFRSF13B/TACI @VARIANT$ mutation appears to demonstrate a gene dosage effect on serum IgG levels.",5671988,TCF3;100147220,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Among these four mutations, while the @VARIANT$ variant in @GENE$ is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.503T>G;tmVar:c|SUB|T|503|G;HGVS:c.503T>G;VariantGroup:9;CorrespondingGene:4040,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the @VARIANT$ of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Six variants in @GENE$ occurred de-novo, three of which were not previously described: @VARIANT$.(Asp1079Alafs*25), c.8860G>T p.(Glu2954*), and @VARIANT$. One de-novo and novel variant was also detected in @GENE$: c.992G>A p.(Cys331Tyr).",7224062,PKD1;250,PKD2;20104,c.3236del p;tmVar:c|DEL|3236|P;HGVS:c.3236delP;VariantGroup:47;CorrespondingGene:5310,c.9201+1G>A;tmVar:c|SUB|G|9201+1|A;HGVS:c.9201+1G>A;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,0
"Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation.       Variants in the @GENE$ gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2).",6707335,SQSTM1;31202,KIF5A;55861,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Digenic inheritance of @GENE$ and MUTYH variants in familial colorectal cancer Abstract We describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding MSH6 @VARIANT$ and @GENE$ @VARIANT$ in, at least, three CRC patients diagnosed before 60 years of age.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0
"Detection of mutations in @GENE$ and @GENE$ in group I are relatively common in East Asian populations, including Koreans, indicating that application of panel sequencing covering the genes prioritized based on the ethnicity-specific prevalence would be effective for identifying GJB2 single heterozygotes with severe to profound SNHL in Koreans. For the family SH60 with a most likely genetic etiology but without a clear result after TES, whole exome sequencing can be used for definitive molecular diagnosis. This family SH60 segregates prelingual or perilingual severe to profound SNHL, likely in an autosomal dominant fashion, although prelingual SNHL of SH60-136 was caused by autosomal recessive mutations in other deafness genes (Figure 3). Further segregation analyses of the two variants (@VARIANT$ and @VARIANT$) among the six family members of SH60 as well as clinical evaluations including audiograms excluded both p.R143W of GJB2 and p.D771N of WFS1 as a molecular etiology of SH60-136.",4998745,MYO15A;56504,TMC1;23670,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6.",6610752,LQT2;201,KCNE2;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Somatic overgrowth associated with homozygous mutations in both @GENE$ and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ @VARIANT$ (p.M400I) and MAN1B1 c.1000C>T (@VARIANT$), associated with congenital birth defects in two patients from a consanguineous family.",4853519,MAN1B1;5230,SEC23A;4642,c.1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,p.R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene. Variants in the DYNC1H1 gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the DYNC1H1 gene in fALS and sALS patients, suggesting its role in ALS. Based on our findings, we strengthen the potential link between DYNC1H1 variants and ALS.     Given that there are genetic and symptomatic overlaps among many neurodegenerative diseases, it has been suggested that causative variants might play roles in multiple disorders. Two heterozygous variants (@VARIANT$ and R166C) were detected in the GBE1 gene.",6707335,MATR3;7830,DYNC1H1;1053,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,H398R;tmVar:p|SUB|H|398|R;HGVS:p.H398R;VariantGroup:18;CorrespondingGene:2632;RS#:755004170;CA#:2499769,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (@VARIANT$; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in @GENE$. Mutation name is based on the full-length @GENE$ (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A13;7523,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: @VARIANT$, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,TRPV4;11003,MRPL15;32210,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,c.1966C>T;tmVar:c|SUB|C|1966|T;HGVS:c.1966C>T;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"                                 CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 @VARIANT$ and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of @GENE$ channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A p.R1865H reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 p.307_308del and @GENE$ @VARIANT$ by WES and predisposing genes analyses.",8739608,Kv11.1;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; @VARIANT$); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,0
"Variant in TYRO3 (@VARIANT$; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, @GENE$, LRP4, @GENE$, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well. No potentially pathogenic rare variant was identified. In order to identify variant(s) in other genes which might influence the expressivity of WS phenotype in our cases, exome data was filtered by using an unbiased and hypothesis-free approach. A rare missense variant (c.101T>G; @VARIANT$) in the C2orf74 gene was identified in both affected individuals.",7877624,ZNRF3;46592,LRP5;1746,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (@VARIANT$ or @VARIANT$); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including @GENE$, TG, @GENE$, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TPO;461,DUOX2;9689,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,0
"Most had @GENE$ repeat expansion combined with another mutation (e.g. VCP R155H or TARDBP A321V; Supplementary Table 6). A single control also had two mutations, @VARIANT$ in @GENE$ and @VARIANT$ in TARDBP.",5445258,C9orf72;10137,ALS2;23264,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G).",3125325,USH2A;66151,CDH23;11142,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, @VARIANT$, p.Tyr27His), @GENE$ (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, @VARIANT$, p.Arg896Trp), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and c.824G>A; p.Trp275X of TACR3).,3888818,TACR3;824,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
GFP-@GENE$ R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-@GENE$ @VARIANT$ with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2).,5953556,CYP1B1;68035,TEK;397,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo @GENE$ @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,VAPB;36163,FUS;2521,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 3;7338,GJB6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in @GENE$ (@VARIANT$; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.",7877624,EDN3;88,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling.",6161649,ENG;92,SCUBE2;36383,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"14 ,  15 The @GENE$ variant is the most common pathogenic variant found in the Netherlands. 2                       The digenic inheritance of @GENE$ and MUTYH variants. A, The pedigree shows the coinheritance of the monoallelic variants which encode MSH6 p.Thr1100Met and MUTYH @VARIANT$ in a family affected by colorectal cancer. All spouses were unrelated and unaffected by cancer. Genotypes: MSH6 p.Thr1100Met (@VARIANT$; blue); MUTYH p.Tyr179Cys (Y179C; green); -, wild type.",7689793,MUTYH;8156,MSH6;149,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,T1100M;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB2;2975,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
" Finally, a subject with the heterozygous p.R143W mutation in GJB2 (SH60-136) carried a p.D771N variant in @GENE$ (WFS1) (NM_001145853) according to TES. However, neither @VARIANT$ in @GENE$ nor @VARIANT$ in WFS1 was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).",4998745,Wolfram syndrome 1;4380,GJB2;2975,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"@VARIANT$ carriers required different surgical procedures for correct IOP control (Table 2). This nucleotide substitution also mapped at @GENE$-@GENE$ intron 1 (@VARIANT$) and the regulatory feature (promoter) (Fig 1C), and it was inferred to produce a low functional effect on FOXC2 and a modifier outcome on both FOXC2-AS1 and the overlapping promoter.",6338360,FOXC2;21091,AS1;736,p.(S36S);tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260,n.145+174G>A;tmVar:n|SUB|G|145_174|A;VariantGroup:14;CorrespondingGene:5729,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, @GENE$, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,TYRO3;4585,RNF43;37742,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"G112A (@VARIANT$) variant has been reported to reduce KCNH2 and KCNQ1 channel currents, enhance KCNH2 susceptibility to QT-prolonging factors, and increase the risk for LQTS, atrial fibrillation, and heart failure. Bioinformatic analysis predicted that KCNE1-G38S was ""tolerated"" and @GENE$-C108Y was ""damaging"", whereas divergent results were obtained for KCNQ1-R583H and KCNH2-K897T, i.e., some programs considered these variants ""damaging"" and others as ""benign"" (Table 2). Moreover, the MAF of KCNQ1-p.R583H was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and @GENE$-p.G38S were much larger (0.187 and 0.352, respectively). KCNH2-p.@VARIANT$ is not reported in the ExAC database.",5578023,KCNH2;201,KCNE1;3753,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in MYD88 gene and a homozygous splice-donor mutation (@VARIANT$) in CARD9 gene. (D) Western Blot of CARD9 and @GENE$ proteins performed on PBMC, EBVB, and PHA derived T cell lines. (E) TNFalpha production by monocytes after LPS stimulation (mean +- SEM of n = 2). (F) Phenotypic analysis of iDC and @GENE$ differentiated in vitro.",6383679,MYD88;1849,mDC;7529,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"  Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (@VARIANT$); P1, P2: thyrotropin >100 microU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (@VARIANT$) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred. Conclusion: This is a report of digenic mutations in DUOX1 and @GENE$ in association with CH, and we hypothesize that the inability of @GENE$ to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype.",5587079,DUOX2;9689,DUOX1;68136,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with VAPB p.M170I and TAF15 @VARIANT$ with SETX p.I2547T and SETX p.T14I).",4293318,VAPB;36163,FUS;2521,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and @GENE$ c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,DVL3;20928,SCRIB;44228,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD6;2617,FAT4;14377,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
    CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in @GENE$ and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in @GENE$ (Table 2).,7549550,MYOD1;7857,MEOX1;3326,c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,1
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ p.M170I and TAF15 @VARIANT$ with @GENE$ @VARIANT$ and SETX p.T14I).,4293318,VAPB;36163,SETX;41003,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (@GENE$ @VARIANT$ at a rate of 4.95 x 10-5, @GENE$ @VARIANT$ at a rate of 8.24 x 10-6).",7463850,EHMT1;11698,MFSD8;115814,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,c. 353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"Finally, as regards the USH3 patients, biallelic mutations in @GENE$ and monoallelic mutations in VLGR1 or WHRN were found in three patients, two patients, and one patient, respectively. One USH1 and two USH2 patients were heterozygotes for mutations in two or three USH genes, suggesting a possible digenic/oligogenic inheritance of the syndrome. In the USH2 patients, however, segregation analysis did not support digenic inheritance. Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in MYO7A (p.K268R), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23.",3125325,USH2A;66151,CDH23;11142,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"This patient was subsequently found to carry a coexisting TIA1 variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different @GENE$ mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,TIA1;20692,SQSTM1;31202,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,1
"SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for @GENE$ and KCNH2 mutations. @GENE$ @VARIANT$ and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4).",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Since @GENE$ is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ TTC26 proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ FLNB proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,0
"RESULTS Mutations at the gap junction proteins Cx26 and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Moderate iodine deficiency in association with double heterozygosity for @GENE$ and @GENE$ mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous DUOX2 nonsense mutation (@VARIANT$, p. R434*).",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,0
"DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. (C) The EDA mutation c.252DelT and WNT10A mutation @VARIANT$ were found in patient S1, who inherited the mutant EDA allele from his mother; @GENE$ mutations in the parents could not be analyzed.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"@GENE$ forms a complex with VEGF and VEGFR2 and acts as a coreceptor to enhance VEGF/VEGFR2 binding, thus stimulating VEGF signalling (figure 3). The c.1592G>A (p.Cys531Tyr) SCUBE2 variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant c.1694G>A (@VARIANT$) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/@GENE$ signalling (figure 3).",6161649,SCUBE2;36383,Akt;3785,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,0
"Three variants in three genes were rare, including the PROKR2 gene mutation [p.(Lys205del)], a novel heterozygous missense variant [@VARIANT$; p.(Glu436Lys)] in the SEMA7A gene (NM_001146029), as well as a splice site variation in the PLXNA1 gene (NM_032242; MAF = 0.03 in GnomAD). The SEMA7A gene variant was predicted as a VUS according to Varsome, whereas the @GENE$ gene variation was classified as benign. The SEMA7A variant [@VARIANT$] was absent in the 92 exomes of our local database (Supplementary Table 8). The ORVAL prediction revealed five pathogenic variant pairs (confidence interval = 90-95%) involving DUSP6, ANOS1, @GENE$, PROP1, PLXNA1, and SEMA7A genes (Table 3 and Supplementary Table 9).",8446458,PLXNA1;56426,DCC;21081,c.1801G > A;tmVar:c|SUB|G|1801|A;HGVS:c.1801G>A;VariantGroup:2;CorrespondingGene:8482;RS#:750920992;CA#:7656750,p.(Glu436Lys);tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of USH2A (NM_007123), R5143C, C4870F, and @VARIANT$ with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and @GENE$ (ANK1) identified in SH 94-208).",4998745,USH2A;66151,Ankyrin 1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,G805A;tmVar:c|SUB|G|805|A;HGVS:c.805G>A;VariantGroup:14;CorrespondingGene:7399;RS#:587783023;CA#:270788,0
"However, the proband's younger brother and father were heterozygous carriers of the @VARIANT$ mutation in the @GENE$ gene while they also carried the p.R1141X mutation in the @GENE$ gene; they did not display any signs of cutaneous findings or hematologic disorder.       Assay of gamma-glutamyl carboxylase activity Previous studies have clearly demonstrated that the @VARIANT$ mutation in the ABCC6 gene in heterozygous carriers does not cause PXE.",2900916,GGCX;639,ABCC6;55559,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Sequences of orthologs and predicted 2D structure of human @GENE$ protein. (A) The alignment of orthologs of the human WNT10A protein. The @VARIANT$ and G213 residues are represented by arrowheads. (B) The predicted 2D structure of human WNT10A protein. The R171 and G213 residues are in yellow. The 3D structure of EDA is shown in Figure 4. The @VARIANT$ residue is located at the interface of two trimers. When G257R mutation happened, the side chain volume significantly enlarged, making it possible to form interaction with the R289 in adjacent trimer and abolish the stabilization of EDA. I312 is located at the outer surface of the three monomers. An I312M mutation could affect the interactions of EDA with its receptors. Structure analysis of mutant residues in the three-dimensional EDA trimer. The EDA trimer is shown as a ribbon with relevant side chains rendered in spheres. The G257 and I312 residues are in yellow and blue, respectively. The side chain of the R289 residue is represented by a colored stick. (A) The planform of the EDA trimer. (B) The side view of the @GENE$ trimer.",3842385,WNT10A;22525,EDA;1896,R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555,G257;tmVar:c|Allele|G|257;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) GBE1 R524Ter; 2) PCCB G407RfrTer14; 3) NUBPL IVS8DC; 4) OAT @VARIANT$. Two additional variants, p. T4823 M in @GENE$ and @VARIANT$ in @GENE$, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,RYR1;68069,CACNA1S;37257,"Y299Ter;tmVar:p|SUB|Y|299,ER|T;HGVS:p.Y299,ERT;VariantGroup:10;CorrespondingGene:4942",p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0
"II: 1 carried the digenic heterozygous mutations of @GENE$ @VARIANT$ and SCN5A p.R1865H. I: 1 and II: 2 were heterozygous for @GENE$ @VARIANT$. Except II: 1, other family members did not carry KCNH2 mutation.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and @GENE$ @VARIANT$. Both mutations are novel and whilst a different mutation, R80W, has been reported in HNF4A, further evidence to support the pathogenicity of E508K is lacking.",4090307,HNF1A;459,HNF4A;395,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,R80Q;tmVar:p|SUB|R|80|Q;HGVS:p.R80Q;VariantGroup:2;CorrespondingGene:3172,1
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, @VARIANT$, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,c.379T>A;tmVar:c|SUB|T|379|A;HGVS:c.379T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered DFNB1 without TES were found to be @GENE$, @GENE$, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES.",4998745,DFNB7/11;23670,DFNB3;56504,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Mutagenesis Sequence variants @GENE$-c.G323A (@VARIANT$) and @GENE$-@VARIANT$ (p.R583H) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,1
"Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and KCNQ1-c.G1748A (@VARIANT$) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously. Primers used for mutagenesis are available upon request. The @GENE$-WT, @GENE$-WT, and mutant coding sequences were engineered in bicistronic mammalian vectors pIRES2-EGFP (Biosciences-Clontech, Palo Alto, CA, USA).",5578023,KCNH2;201,KCNQ1;85014,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Both mutations are novel and whilst a different mutation, R80W, has been reported in HNF4A, further evidence to support the pathogenicity of @VARIANT$ is lacking. The siblings we describe with the @GENE$ P291fsinsC and @GENE$ @VARIANT$ mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic.",4090307,HNF1A;459,HNF4A;395,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0
"The localization of the so far only GATA4 mutation reported to cause a 46,XY DSD phenotype (@VARIANT$) is given in bold and its localization is also highly conserved. Additional (DSD) Gene Variations Identified by Next Generation Sequencing (NGS) In case 1, additional targeted exome sequencing of 4,813 disease-causing genes, containing 94 genes related to DSD, did not reveal any further sequence variant. In cases 2 and 3, without CHD, DSD targeted gene sequencing identified two additional gene variations. Case 2 revealed a novel, heterozygous C to G change at position 5660 (c.5560C>G; @VARIANT$) of the LDL receptor-related protein 4 (@GENE$) gene (OMIM 604270). This gene variant was also found in the mother and the maternal uncle. In case 3, a heterozygous change of cytosine to thymine was found at location 1660 of the @GENE$ gene (OMIM 152790).",5893726,LRP4;17964,LHCGR;37276,p.Gly221Arg;tmVar:p|SUB|G|221|R;HGVS:p.G221R;VariantGroup:4;CorrespondingGene:2626;RS#:398122402(Expired),p.Ser1887Cys;tmVar:p|SUB|S|1887|C;HGVS:p.S1887C;VariantGroup:2;CorrespondingGene:4038;RS#:73460019,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB6;4936,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the @GENE$ pathway given the deleterious nature of both variants (Table 2).",7549550,RIPPLY1;138181,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases. Location analysis of missense changes showed that p.G1108E was located very close to the fourth PDZ domain (1109-1192) of SCRIB. The PDZ domains of human SCRIB are required for correct localization and physical interaction with other proteins, such as the core PCP protein VANGL2, which is required for transducing PCP signals. Herein we demonstrate that SCRIB variants combined with variants among other PCP genes might be associated with the observed NTD phenotypes in humans. However, pathogenic effect of these variants on protein function or on neural tube development need to be investigated in the future.   No reports are available in the literature on the contribution of digenic variants of @GENE$ and @GENE$ gene in the pathogenesis of NTDs.",5966321,CELSR1;7665,DVL3;20928,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"GJB2 = gap junction protein beta 2, SNHL = sensorineural hearing loss, @GENE$ = wolfram syndrome 1.             Single Heterozygous GJB2 Mutant Allele Possibly Contributing to Deafness via Digenic Inheritance: Double Heterozygosity with Additional Mutation in Other Deafness Genes (Group II) Interestingly, two subjects (SH107-225 and SH175-389) showed double heterozygosity for a GJB2 mutation and another likely pathogenic mutation in another deafness gene. We detected a de novo Microphthalmia-associated transcription factor (@GENE$) (NM_000248) variant, p.R341C, in one of the @VARIANT$ carriers (SH107-225) (Figure 4A). She inherited c.235delC of GJB2 from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). The @VARIANT$ residue of MITF is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C).",4998745,WFS1;4380,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.",5505202,PROKR2;16368,EMX1;55799,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$).",5887939,CELSR1;7665,DVL3;20928,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS2;12122,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
This indicates that neither @VARIANT$ in @GENE$ nor @VARIANT$ in @GENE$ contributed to SNHL in SH60-136 and that p.R143W in GJB2 was an incidentally detected variant in this subject.,4998745,GJB2;2975,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"@VARIANT$ lies within a cytoplasmic domain between the 5th-6th transmembrane domains of this G-protein coupled receptor, thereby predicting the loss of 191AA from codons 275-465 and truncating ~40% of the C-terminus (Figure 1C). He had no mutations in @GENE$, @GENE$, FGFR1, PROK2, PROKR2, TAC3, KAL1, GNRHR, GNRH1, or KISS1R. Unfortunately, in all three probands with NELF mutations, no other family members were available for de novo or segregation analysis. Discussion Our findings indicate that NELF is likely to be causative in IHH/KS. Previously, Miura et al demonstrated a heterozygous c.1438A>G (p.Thr480Ala) NELF variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to @VARIANT$ ;p.Thr478Ala from NP_056352).",3888818,CHD7;19067,FGF8;7715,Trp275;tmVar:p|Allele|W|275;VariantGroup:1;CorrespondingGene:6870;RS#:144292455,c.1432A>G;tmVar:c|SUB|A|1432|G;HGVS:c.1432A>G;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ @VARIANT$, and @GENE$ p.T1249I.",4293318,ANG;74385,DCTN1;3011,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,0
"The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene. Variants in the DYNC1H1 gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the @GENE$ gene in fALS and sALS patients, suggesting its role in ALS. Based on our findings, we strengthen the potential link between DYNC1H1 variants and ALS.     Given that there are genetic and symptomatic overlaps among many neurodegenerative diseases, it has been suggested that causative variants might play roles in multiple disorders. Two heterozygous variants (H398R and @VARIANT$) were detected in the GBE1 gene.",6707335,MATR3;7830,DYNC1H1;1053,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,R166C;tmVar:p|SUB|R|166|C;HGVS:p.R166C;VariantGroup:21;CorrespondingGene:2632;RS#:376546162;CA#:2499951,0
"Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of @GENE$ function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 p.T410M mutations.",7067772,pendrin;20132,EPHA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"However, mutations identified in SASH3, @GENE$, NUP214, and MAN1B1 were rare and not previously seen in our exome database (>1400 exomes), in dbSNP (Database for Short Genetic Variations), in 1000 Genomes Project, nor in the NHLBI (National Heart, Lung, and Blood Institute) exome databases, with minor allele frequencies of 0 (Table 2). Three independent bioinformatics algorithms, SIFT, PolyPhen-2, and MutationTaster predicted both the 284G>A MUM1L1 and the @VARIANT$ @GENE$ mutations as benign, suggesting that mutations in these genes are unlikely to be responsible for abnormalities found in our affected patients. The @VARIANT$ SASH3 mutation was predicted to be benign by SIFT, possibly damaging by PolyPhen-2 (P = 0.463), and damaging by MutationTaster (P = 0.999).",4853519,SEC23A;4642,NUP214;38008,2701C>T;tmVar:c|SUB|C|2701|T;HGVS:c.2701C>T;VariantGroup:2;CorrespondingGene:8021,790A>G;tmVar:c|SUB|A|790|G;HGVS:c.790A>G;VariantGroup:3;CorrespondingGene:11253;RS#:1388124110,0
"To examine whether @GENE$ is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Sequencing of the proband's sister's and her aunt's @GENE$ gene revealed the presence of eight heterozygous polymorphisms in the exons 7-19. This finding argues against large allelic deletions at the 5' half of the gene which might not be detectable by the mutation detection strategy employed in our study.           Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the @GENE$ and VKORC1 genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (@VARIANT$ A) resulting in substitution of a valine by methionine at position 255 (@VARIANT$) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b).",2900916,ABCC6;55559,GGCX;639,c.791G;tmVar:c|Allele|G|791;VariantGroup:5;CorrespondingGene:368;RS#:753836442,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,VPS13C;41188,UNC13B;31376,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (@VARIANT$;p.I436V) mutation inherited from an unaffected father. Mutant @GENE$ loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus.",5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"Given the reported normal function of pendrin @VARIANT$ and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that @GENE$ could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.",7067772,pendrin;20132,EphA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The @VARIANT$ and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2). While @GENE$ blocks VEGF/VEGFR2 signalling, RASA1 modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,ENG;92,TIMP3;36322,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,0
"Therefore, in this study, SCN5A p.R1865H may be the main cause of sinoatrial node dysfunction, whereas @GENE$ p.307_308del only carried by II: 1 may potentially induce the phenotype of LQTS. However, it was hard to determine whether the coexisting interactions of KCNH2 @VARIANT$ and @GENE$ p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Two different @GENE$ mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,1
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(Cys331Thr) in @GENE$. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in @GENE$, p.(@VARIANT$), and a second variant in PKD2, p.(@VARIANT$).",7224062,PKD2;20104,PKD1;250,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(Ser123Thr), and a second variant in PKD2, p.(Arg872Gly). Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(Ser872Gly) variant in PKD1, while only one fetus inherited the p.(@VARIANT$) PKD2 variant.",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (c.1892C>T).",5887939,PRICKLE4;22752,CELSR2;1078,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"In this family, the patient (II: 1) with digenic heterozygous mutations of KCNH2 @VARIANT$ and @GENE$ @VARIANT$ presented the earliest phenotype of LQTS, and she suffered from syncope, torsades de pointes, and ventricular fibrillation more frequently at rest, whereas the members (I:1 and II:2) without @GENE$ p.307_308del showed normal QT intervals and cardiac function.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD.  Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.2857A > G @VARIANT$) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.@VARIANT$ p. S159G) and rs2229113 (c.1051 G > A p.G351R), have already been described in the literature.",3975370,IL10RA;1196,IL10RB;523,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,0
Future studies will focus on determining how double homozygous mutations in @GENE$ (@VARIANT$) and MAN1B1 (@VARIANT$) result in increased intracellular pro-@GENE$ levels and increased pro-COLA1 secretion.,4853519,SEC23A;4642,COL1A1;73874,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0
"MTHFR, methylenetetrahydrofolate reductase                             One individual (283F06) was heterozygous for a novel missense variant in the catalytic N-terminal domain of the methylenetetrahydrofolate reductase (MTHFR) gene (c.601C>T; @VARIANT$) (Figure 2D), which was predicted to be damaging by all 6 mutation predictors tested (Table 1). This individual was also heterozygous for the common @GENE$ c.677C>T variant, and also carries a rare @GENE$ (GLDC) @VARIANT$ missense variant, possibly indicating a compromised FOCM in this patient.",5887939,MTHFR;4349,glycine decarboxylase;141,p.His201Tyr;tmVar:p|SUB|H|201|Y;HGVS:p.H201Y;VariantGroup:15;CorrespondingGene:2068;RS#:756740686,c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332,0
"Sequence alterations were detected in the COL6A3 (@VARIANT$), RYR1 (rs143445685), @GENE$ (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,CAPN3;52,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form.",6707335,GRN;1577,SIGMAR1;39965,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"25  The RYR3 (NM_001036: c.7812C > G, @VARIANT$) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in @GENE$ might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25  The contribution of the genetic variants, other than @GENE$ and MUTYH, to cancer risk cannot be completely excluded.",7689793,CAPN9;38208,MSH6;149,p.Asn2604Lys;tmVar:p|SUB|N|2604|K;HGVS:p.N2604K;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,0
"Importantly, he had no coexistent mutations in CHD7, FGF8, FGFR1, PROK2, @GENE$, @GENE$, TACR3, KAL1, GNRHR, GNRH1, or KISS1R. The second patient (KS male C7) had a heterozygous c.757G>A (p.Ala253Thr) mutation (Figure 1; Table 1) affecting a completely conserved Ala253 residue (Figures S1-4). Using multiple sequence alignment (ESPRESSO), a protein model for the N-terminus was constructed. Both SSPIDER and INTERPROSURF analysis (Figure S4) suggest functional importance for Ala253; and SIFT predicts a deleterious effect for p.Ala253Thr. Although p.Ala253Thr did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This @VARIANT$ mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously.",3888818,PROKR2;16368,TAC3;7560,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants @VARIANT$ (p.Gly505Ser) in EHMT1 and @VARIANT$ (p.Asn118Ser) in MFSD8. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (@GENE$ c.1513G > A at a rate of 4.95 x 10-5, @GENE$ c. 353A > G at a rate of 8.24 x 10-6).",7463850,EHMT1;11698,MFSD8;115814,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the AMH promoter, and failed to bind cofactor @GENE$. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation p.Cys238Arg, but no effect on transactivation activity on the @GENE$ promoter for GATA4 variants p.Pro226Leu and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of GATA4 (Figure 1), only Gly221 and @VARIANT$ are close to Zn binding sites. The Gly221 is not directly involved in Zn binding but is situated next to Cys220 which binds the Zn atom, and therefore, the mutation Gly221Arg will disrupt the Zn binding, leading to a non-functional GATA4. The Cys238 binds Zn and its mutation to arginine leads to loss of Zn binding (Figure 4). GATA4 regulates the expression of multiple genes coding for hormones or components of the steroidogenic pathway during testis development and function. In Gata4ki mice with @VARIANT$ mutation interaction of Gata4 with cofactor Fog is abrogated, and consequently animals display anomalies of testis development.",5893726,FOG2;8008,CYP17;73875,Cys238;tmVar:p|Allele|C|238;VariantGroup:0;CorrespondingGene:2626,p.Val217Gly;tmVar:p|SUB|V|217|G;HGVS:p.V217G;VariantGroup:6;CorrespondingGene:14463,0
"In our study, we identified four genetic variants in three genes (@GENE$-p.R583H, @GENE$-p.C108Y, KCNH2-@VARIANT$, and KCNE1-@VARIANT$).",5578023,KCNQ1;85014,KCNH2;201,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"  Digenic inheritances of GJB2/MITF and @GENE$/@GENE$ (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,GJB2;2975,GJB3;7338,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 156 to Cys.",3842385,EDA;1896,WNT10A;22525,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The @VARIANT$ and R393Q variants are known variants reported by other study groups.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"Including the validation cohort, @VARIANT$, IVS28+1G>T, p.R885Q, p.L1343F, and p.R683L were also common in Xinjiang DH patients. TG mutations were the second most prevalent genetic alterations in DH: five different heterozygous variants were found in 5/21 patients (23.8%), and these often cooccurred with DUOX2 or DUOXA2 mutations. DUOX2 and TG mutation locations varied in the corresponding proteins (Figure 2). Additionally, three DUOXA2 variants were found in 3/21 patients (14%), and a known heterozygous variant in SLC26A4 was found in one patient. No mutations in @GENE$, TPO, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (p.M927V) in one patient, (2) @GENE$:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,SLC5A5;37311,DUOX2;9689,p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS6;10318,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"GFP-CYP1B1 @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-@GENE$ E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant @GENE$ and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK. The residues @VARIANT$, I148, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103;tmVar:p|Allele|E|103;VariantGroup:2;CorrespondingGene:7010;RS#:572527340,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ p.M170I and TAF15 @VARIANT$ with @GENE$ p.I2547T and SETX @VARIANT$).,4293318,VAPB;36163,SETX;41003,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"The brother who is homozygous (II.4) for the TNFRSF13B/@GENE$ @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the @GENE$ @VARIANT$ mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"RESULTS Mutations at the gap junction proteins @GENE$ and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The mother and son reported by Beijers et al. were heterozygous for HNF1A @VARIANT$ and HNF4A H214Y, but the G31D substitution has subsequently been identified in 7/4300 European exomes (Exome variant server, NHLBI GO Exome Sequencing Project http://evs.gs.washington.edu/EVS/). It is therefore unlikely to be causative of MODY. The proband described by Forlani et al. was heterozygous for HNF1A E508K and HNF4A R80Q. Both mutations are novel and whilst a different mutation, R80W, has been reported in @GENE$, further evidence to support the pathogenicity of E508K is lacking. The siblings we describe with the @GENE$ P291fsinsC and HNF4A @VARIANT$ mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic.",4090307,HNF4A;395,HNF1A;459,G31D;tmVar:p|SUB|G|31|D;HGVS:p.G31D;VariantGroup:4;CorrespondingGene:6927;RS#:137853247;CA#:124487,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
"A male (ID104) was found to have a heterozygous missense variant @VARIANT$ (p.Lys330Met) in EHMT1 and a missense variant c.1777C > G (p.Leu593Val) in SLC9A6. Limited clinical information was available about this male. The variant in @GENE$ was absent from the ExAC and gnomAD databases. De novo variants in EHMT1 have been reported in individuals with autism, but developmental regression has not been reported. Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.",7463850,EHMT1;11698,SLC9A6;55971,c.989A > T;tmVar:c|SUB|A|989|T;HGVS:c.989A>T;VariantGroup:1;CorrespondingGene:79813;RS#:764291502;CA#:5375151,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,Arg at residue 156 to Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"In those samples, no mutation was detected on the second allele either in @GENE$-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,GJB6;4936,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"Among the six variants (Table 2), two are missense variants in the RNA Binding Motif Protein 43 (@GENE$) gene (@VARIANT$) and the dermatopontin (@GENE$) gene (@VARIANT$).",5611365,RBM43;12715,DPT;1458,p.V34L;tmVar:p|SUB|V|34|L;HGVS:p.V34L;VariantGroup:31;CorrespondingGene:375287;RS#:147060862;CA#:1902988,p.Y149C;tmVar:p|SUB|Y|149|C;HGVS:p.Y149C;VariantGroup:15;CorrespondingGene:1805;RS#:777651623;CA#:1231264,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The p.Ile312Met (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,1
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,1
"(E) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in EDA and @VARIANT$ in @GENE$ were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 3;7338,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,1
"During mesoderm development, the expression of @GENE$ is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.   CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified.",7549550,MEOX1;3326,MYOD1;7857,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with VAPB p.M170I and @GENE$ @VARIANT$ with SETX p.I2547T and SETX @VARIANT$).,4293318,ANG;74385,TAF15;131088,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, GRIN2A c.28C > A (@VARIANT$) and PLXNB2 @VARIANT$ (p.Arg248Cys). The variant in GRIN2A was novel and was predicted to be damaging using both SIFT and PolyPhen. Heterozygous @GENE$ germline variants are considered to be major genetic causes of Landau Kleffner syndrome, which is characterized by speech impairment and focal epilepsy. Two unrelated males in our cohort were found to harbor the variant GRIN2A c.28C > A. Both were referred for evaluation at 3 years of age and had language development arrest and regression. In addition, one of the males (ID113) had hydrocephaly and showed an increase in emotional negativity and stereotypies. The other male (ID090) experienced sleep disturbance. The @GENE$ gene is important for brain development but has not been associated with any disorder.",7463850,GRIN2A;645,PLXNB2;66630,p.Leu10Met;tmVar:p|SUB|L|10|M;HGVS:p.L10M;VariantGroup:0;CorrespondingGene:2903,c.742C > T;tmVar:c|SUB|C|742|T;HGVS:c.742C>T;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0
"Given their offspring was mutation carriers, we might infer that II-4 and III-1 also harbored the CACNA1C-@VARIANT$ mutation. Notably, not all @GENE$-Q1916R carriers (II-3, II-6, III-4, III-5, III-7, IV-1, IV-3, IV-4 and obligate carriers II-4 and III-1) manifested the positive phenotypes (ER pattern in ECG or nocturnal SCD). This phenotypic incomplete penetrance might be modified by @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In this study, we speculated that, during the repolarization phase, the inadequate inward current caused by the detrimental @GENE$-@VARIANT$ mutation might be partly compensated by the persistent inward tail INa produced by the SCN5A-R1193Q channel. That may be how @GENE$-@VARIANT$ plays a protective role against the detrimental phenotype induced by the CACNA1C-Q1916R mutation.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"                                 Quantitation of epistatic interactions of @GENE$ and TACI mutations showing a greater net effect than the sum of each individual mutation. Total Serum Ig, clinical score and @GENE$/TACI @VARIANT$ and TCF3 @VARIANT$ genotype for each family member, as indicated.",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T161fsX191;tmVar:p|FS|T|161||191;HGVS:p.T161fsX191;VariantGroup:5;CorrespondingGene:6929,0
The p.Ala349Thr (@VARIANT$) mutation in exon 9 of @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of @GENE$ were detected.,3842385,EDA;1896,WNT10A;22525,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and @GENE$/TACI C104R mutations. Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI @VARIANT$ mutation.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Causative heterozygous mutations in @GENE$ (@VARIANT$/c.1145A > G) and @GENE$ (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.,7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that @GENE$ may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between p.R2003H FLNB and p.Y437F @GENE$ (figure 3D).",7279190,FLNB;37480,OFD1;2677,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between FLNB and @GENE$. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and @VARIANT$ TTC26 proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ @GENE$ proteins, respectively (figure 2D, E).",7279190,TTC26;11786,FLNB;37480,p.R197C;tmVar:p|SUB|R|197|C;HGVS:p.R197C;VariantGroup:32;CorrespondingGene:79989,p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,0
"Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,1
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of GJB3 that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the A194T of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"One patient (f93-80) had a novel @GENE$ missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant @VARIANT$).",5887939,PTK7;43672,FAT4;14377,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b). These EPHA2 mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying @VARIANT$ of @GENE$ was previously reported.",7067772,EPHA2;20929,SLC26A4;20132,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,0
"Among the 8 novel variants, 4 were classified as P (@VARIANT$ and p.K618* in @GENE$, p.T803fs in @GENE$) or LP (@VARIANT$ in DUOX2), the other were classified as VUS.",7248516,TSHR;315,DUOX2;9689,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ c.4333A>G, @VARIANT$), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,rs761703397;tmVar:rs761703397;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,TOR2A;25260,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"The reasons for the fact that the proband's father and her brother were heterozygous carriers of mutations in the @GENE$ gene (@VARIANT$) and the @GENE$ gene (p.S300F) yet did not display any cutaneous findings are not clear. Specifically, while both GGCX mutations resulted in reduced enzyme activity, the reduction in case of protein harboring the p.S300F mutation was more pronounced than that of @VARIANT$. In this context, it should be noted that the substrate employed in the carboxylase assay is a pentapeptide, Phe-Leu-Glu-Glu-Leu, and it is possible that the activity measurements if done on full-length MGP as substrate would show differential activity with these two mutant enzymes.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin @VARIANT$, pendrin S166N, and pendrin @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The @GENE$ gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations.",8446458,PROKR2;16368,DUSP6;55621,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (@VARIANT$) in the @GENE$ gene. Moreover, a rare heterozygous, missense damaging variant (c.101T>G; @VARIANT$) in the C2orf74 has also been identified. The @GENE$ is an uncharacterized gene present in the linked region detected by DominantMapper.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of MSH6 @VARIANT$ protein. In addition, the genetic marker for MAP-tumors (KRAS c.34G > T) was absent in this tumor, which points toward retained MUTYH repair activity. The combined inheritance of both genetic variants could still result in impaired repair of oxidative DNA damage. More extensive somatic mutation analysis to assess this was, however, not possible, because of low quality of the DNA sample and the unavailability of additional tumor material.         Next to MSH6 and MUTYH, CUX1 has been described as a cancer-driving gene. 18  CUX1 is implicated in inflammatory bowel disease and various cancer types, although primarily due to loss-of-function somatic mutations. 18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by @GENE$. 20  The identified @GENE$ (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool.",7689793,OGG1;1909,CUX1;22551,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,MYOD1;7857,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"@GENE$ mutations were the second most prevalent genetic alterations in DH: five different heterozygous variants were found in 5/21 patients (23.8%), and these often cooccurred with DUOX2 or DUOXA2 mutations. DUOX2 and TG mutation locations varied in the corresponding proteins (Figure 2). Additionally, three DUOXA2 variants were found in 3/21 patients (14%), and a known heterozygous variant in SLC26A4 was found in one patient. No mutations in SLC5A5, @GENE$, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: @VARIANT$ (p.Y138X) in one patient.",6098846,TG;2430,TPO;461,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation @VARIANT$ in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (Gly1119Ala)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in @GENE$ were identified.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"(A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes.     ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The p.Ala349Thr (c.1045G>A) mutation in exon 9 of EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in exon 3 of WNT10A were detected.",3842385,EDA;1896,WNT10A;22525,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The @VARIANT$ residue of MITF is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/@GENE$ and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,MITF;4892,GJB3;7338,p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
"Case A was a compound heterozygote for mutations in @GENE$, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in @GENE$. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain.",4470809,OPTN;11085,TBK1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The A194T substitution might cause conformational changes within the @GENE$ molecule or affect the ability of Cx31 to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the Cx26 mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to @VARIANT$ and A194 identified in the families reported here, namely, M163L, R165W, F191L, and A197S in @GENE$ as well as @VARIANT$, S198F and G199R in Cx32, have been reported previously in patients with hearing impairment.",2737700,Cx31;7338,Cx26;2975,N166;tmVar:p|Allele|N|166;VariantGroup:0;CorrespondingGene:2707;RS#:121908851,F193C;tmVar:p|SUB|F|193|C;HGVS:p.F193C;VariantGroup:15;CorrespondingGene:2706,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, @GENE$ = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 6;4936,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and @GENE$ (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,MYOD1;7857,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB3;7338,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"These phenomenon indicate that the mutated SCAP-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated @GENE$ coding protein. AGXT2-c.1103C>T (p.Ala338Val) variant impaired the catabolism of ADMA in EA. hy926 cell lines @GENE$-c.1103C>T (@VARIANT$) variant was introduced into EA.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"We have screened 108 GJB2 heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (@VARIANT$) in one patient, (2) @GENE$:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and @GENE$ @VARIANT$).",4293318,TARDBP;7221,SETX;41003,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"The @VARIANT$ variant in GJB2 occurring in complex heterozygosity with a pathogenic @GENE$ variant, @VARIANT$ from SH175-389, suggests a possible digenic etiology of SNHL involving two different gap junction proteins, Cx26 and Cx31. Large deletions in @GENE$ (del [GJB6-D13S1830] and del [GJB6-D13S1854]) are frequently detected in a trans configuration with a monoallelic GJB2 mutation in certain populations.",4998745,GJB3;7338,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Case A was a compound heterozygote for mutations in @GENE$, carrying the @VARIANT$ nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1. Cases C-E carried heterozygous missense mutations in @GENE$, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain.",4470809,OPTN;11085,TBK1;22742,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The results showed that, in addition to the @GENE$ gene variant [p.(@VARIANT$)], a second variant in c.2803C > T in the CCDC141 gene was involved in the second highest number of pathogenic digenic combinations (15%), with 18 other variants in 13 genes. The CCDC141 variant was found at a homozygous state in the patient HH1 and at a heterozygous state in the asymptomatic cases. Our analysis indicated that the zygosity state of the @VARIANT$ variant in the @GENE$ gene considerably influenced the rate of pathogenic combinations.",8446458,PROKR2;16368,CCDC141;52149,Pro290Ser;tmVar:p|SUB|P|290|S;HGVS:p.P290S;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,0
"Previous studies have shown TNFRSF13B/@GENE$ @VARIANT$ homozygous individuals are able to produce some IgG in vitro with APRIL stimulation alone. This is likely to be augmented by Toll-like receptor signalling with CpG as well as IL-4 and IL-21, in our experiments. As expected, his cells produce greater amounts of IgG through his intact T-cell-dependent pathway. The proband's son (III.1) carrying only the heterozygous @GENE$ @VARIANT$ mutation is also able to produce some IgG in vitro via activation of both pathways, but at much lower levels than his wild-type sister (III.2).",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and @VARIANT$ pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Despite the absence of IgG detected in the supernatants of these cultures, no defect was observed in the generation of isotype switched IgG+ cells in II.2 (carrying both @GENE$/TACI @VARIANT$ and TCF3 @VARIANT$ mutations), compared to III.2, who has neither mutation. Her son, III.1, carrying the @GENE$ T168fsX191 mutation only, also generated a similar proportion of IgG+ switched cells.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in @GENE$ gene and a homozygous splice-donor mutation (@VARIANT$) in @GENE$ gene.,6383679,MYD88;1849,CARD9;14150,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,1
"Co-segregation of TEK p.I148T and @GENE$ @VARIANT$ was observed in two pedigrees and only a representative pedigree is shown. b Chromatograms of the four probands (lower panel) harboring the four different heterozygous TEK mutations. The site of nucleotide change is indicated by an arrow, compared to the corresponding wild-type sequence (upper panel). c TEK protein sequence conservation across different species for the four mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A). The conserved residue for each mutation is highlighted in blue color. d Schematic representation of the TEK and CYP1B1 domains (Ig immunoglobulin, EGF epidermal growth factor, FN fibronectin, TM transmembrane, M membrane, H hinge region) indicating the location of the mutations identified in PCG (color figure online) TEK and CYP1B1 interact in cells. HEK293 were transiently transfected with indicated GFP-CYP1B1 and HA-@GENE$ plasmids.",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Detection of mutations in @GENE$ and @GENE$ in group I are relatively common in East Asian populations, including Koreans, indicating that application of panel sequencing covering the genes prioritized based on the ethnicity-specific prevalence would be effective for identifying GJB2 single heterozygotes with severe to profound SNHL in Koreans. For the family SH60 with a most likely genetic etiology but without a clear result after TES, whole exome sequencing can be used for definitive molecular diagnosis. This family SH60 segregates prelingual or perilingual severe to profound SNHL, likely in an autosomal dominant fashion, although prelingual SNHL of SH60-136 was caused by autosomal recessive mutations in other deafness genes (Figure 3). Further segregation analyses of the two variants (p.R143W and @VARIANT$) among the six family members of SH60 as well as clinical evaluations including audiograms excluded both @VARIANT$ of GJB2 and p.D771N of WFS1 as a molecular etiology of SH60-136.",4998745,MYO15A;56504,TMC1;23670,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"    Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and @GENE$ mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
We identified a novel variant in the @GENE$ gene (c.2857A > G @VARIANT$) and two already described missense variants in the @GENE$ gene (@VARIANT$ and G351R).,3975370,NOD2;11156,IL10RA;1196,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,1
"Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and c.353A > G (@VARIANT$) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The SLC20A2 c.1787A>G (@VARIANT$) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to @GENE$ dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the @GENE$ c.317G>C (@VARIANT$) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,PiT2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother. Proband 17 inherited CHD7 @VARIANT$ and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively.",8152424,DMXL2;41022,CDON;22996,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,0
"In our study, we identified four genetic variants in three genes (@GENE$-@VARIANT$, KCNH2-p.C108Y, @GENE$-p.K897T, and KCNE1-@VARIANT$).",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, @VARIANT$), @GENE$ p.307_308del (NM_001204798, c.921_923del), and DMD @VARIANT$ (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2).",8739608,LAMA2;37306,KCNH2;201,c.G2881A;tmVar:c|SUB|G|2881|A;HGVS:c.2881G>A;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,p.E1028V;tmVar:p|SUB|E|1028|V;HGVS:p.E1028V;VariantGroup:5;CorrespondingGene:3757,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,PRICKLE4;22752,CELSR1;7665,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and @GENE$ p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in @GENE$. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX @VARIANT$ and SETX p.T14I).",4293318,DCTN1;3011,ATXN2;2234,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"We detected a de novo Microphthalmia-associated transcription factor (MITF) (NM_000248) variant, @VARIANT$, in one of the c.235delC carriers (SH107-225) (Figure 4A). She inherited @VARIANT$ of GJB2 from her father and did not have any known large genomic deletions within the @GENE$ locus (Figure 4B). The p.R341 residue of @GENE$ is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C).",4998745,DFNB1;2975,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a @GENE$ (@VARIANT$;p.I436V) mutation inherited from an unaffected father.",5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, @VARIANT$), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS. The novel @GENE$ c.503T>G mutation substitutes the hydrophobic methionine168 for an arginine (p.Met168Arg) and is predicted to be ""probably damaging"", with a PolyPhen-2 score of 1.",8621929,WNT10A;22525,LRP6;1747,rs761703397;tmVar:rs761703397;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"Co-transfection of HEK293 (human embryonic kidney) cells with plasmids encoding recombinant HA-TEK (hemagglutinin-tagged TEK) and GFP-@GENE$ followed by co-immunoprecipitation with anti-GFP-conjugated beads demonstrated that HA-TEK and GFP-CYP1B1 are part of the same complex. As negative control, no interaction was detected between the GFP tag and HA-TEK proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2).",5953556,CYP1B1;68035,TEK;397,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS2;12122,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (@VARIANT$), EPHA2: c.1063G>A (@VARIANT$) and @GENE$: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.434A>T;tmVar:p|SUB|A|434|T;HGVS:p.A434T;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,0
"    A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected.",6707335,alsin;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: c.3299C > T, @VARIANT$) and MUTYH (NM_001128425.1: c.536A > G, @VARIANT$) genes, while the other 20 genes could not be clearly linked to cancer predisposition. The identified MSH6 variant was classified as a variant of uncertain significance (VUS) in the Leiden Open Variant Database and the InSiGHT DNA Variant Database. 14 ,  15 The MUTYH variant is the most common pathogenic variant found in the Netherlands. 2                       The digenic inheritance of @GENE$ and @GENE$ variants.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,0
"(D) Validation by Sanger sequencing of the identified @GENE$ c.[326_327insT;@VARIANT$] and @GENE$ @VARIANT$ mutations in the affected individual, the unaffected sibling and her parents.",5967407,RP1L1;105870,C2orf71;19792,7117C>T;tmVar:g|SUB|C|7117|T;HGVS:g.7117C>T;VariantGroup:3;CorrespondingGene:94137;RS#:759654067;CA#:4623074,c.1535C>A;tmVar:c|SUB|C|1535|A;HGVS:c.1535C>A;VariantGroup:1;CorrespondingGene:388939;RS#:1293811678,1
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,UBQLN2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in @GENE$ and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,MYO7A;219,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"Table 4 shows detailed information on the 10 rare missense variants, including: CELSR1 c.8772G > C (p.Q2924H); CELSR1 c.3364G > A (p.G1122S); CELSR1 c.3169C > T (p.R1057C); CELSR1 c.2305C > T (p.R769W); DVL3 c.443G > A (@VARIANT$); @GENE$ c.1925C > G (p.P642R); SCRIB c.3323G > A (p.G1108E); SCRIB c.3131G > A (p.R1044Q); SCRIB c.1931G > T (@VARIANT$); and @GENE$ c.1853A > G (p.K618R).",5966321,PTK7;43672,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G644 V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"GJB2 Single Heterozygotes where @GENE$ was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected GJB2 Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (@VARIANT$) (rs121908073), and a novel variant, p.W482R of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1).",4998745,DFNB1;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,c.100C>T;tmVar:c|SUB|C|100|T;HGVS:c.100C>T;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002,0
"Moreover, the MAF of KCNQ1-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of @GENE$-p.K897T and @GENE$-@VARIANT$ were much larger (0.187 and 0.352, respectively).",5578023,KCNH2;201,KCNE1;3753,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"Compound heterozygous variants in @GENE$, DSCAM and @GENE$ were retained. In two unrelated patients, AVM106 and AVM285, identical compound heterozygous variants were identified in DSCAML1: c.5783G>A (@VARIANT$) and c.4574G>A (p.Arg1525His), each inherited from heterozygous carrier parents (table 2). Both variants were reported in ExAC with an allele frequency <0.001, and they were predicted in silico to be highly deleterious (GERP++>4 and CADD>30 for both). In patient AVM226, we identified the compound heterozygous variants c.3775G>A (p.Val1259Ile) and c.2966A>T (p.Gln989Leu) in DSCAM (table 2). DSCAML1 and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in PTPN13 (table 2).",6161649,DSCAML1;79549,PTPN13;7909,p.Arg1928His;tmVar:p|SUB|R|1928|H;HGVS:p.R1928H;VariantGroup:5;CorrespondingGene:57453;RS#:1212415588,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"We identified four genetic variants (KCNQ1-@VARIANT$, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, @GENE$-p.R583H and @GENE$-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
   Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the @GENE$ gene and in exon 4 (@VARIANT$; p.Pro291Arg) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the GCK variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B).,8306687,GCK;55440,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"We identified four genetic variants (@GENE$-p.R583H, KCNH2-p.C108Y, @GENE$-p.K897T, and KCNE1-@VARIANT$) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-@VARIANT$, using the whole-cell patch clamp technique.",5578023,KCNQ1;85014,KCNH2;201,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and @GENE$ genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the @GENE$ gene variant [p.(@VARIANT$)].",8446458,PROP1;4558,DUSP6;55621,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein. However, the two rare FUS variants (Y25C and @VARIANT$) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein.",6707335,SPG11;41614,ubiquilin-2;81830,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,P106L;tmVar:p|SUB|P|106|L;HGVS:p.P106L;VariantGroup:7;CorrespondingGene:2521;RS#:374191107;CA#:8023567,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
   Two nucleotide variants in exon 8 (@VARIANT$; p.Glu290*) of the GCK gene and in exon 4 (c.872 C > G; @VARIANT$) of the @GENE$ gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the HNF1A variant was present in the mother (Figure 1B).,8306687,HNF1A;459,GCK;55440,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (@VARIANT$) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD;8321;8323,FZD6;2617,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.655A>G;tmVar:c|SUB|A|655|G;HGVS:c.655A>G;VariantGroup:2;CorrespondingGene:5754;RS#:373263457;CA#:4677776,0
"Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited @GENE$ p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the CCDC88C @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,DCAF17;65979,CHD7;19067,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, @GENE$ and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2).",3125325,USH1G;56113,MYO7A;219,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  @GENE$, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: @VARIANT$, p.Glu274Asp) and the @GENE$ (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS.",7689793,EBNA1BP2;4969,CAPN9;38208,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"This hypothesis was further supported when a patient with Kallmann syndrome was discovered to carry the same PROKR2 heterozygous mutation as our proband, @VARIANT$, in combination with a second heterozygous mutation in FGFR1, c.1810G>A;@VARIANT$ (NM_023110.2), thereby providing evidence for a digenic basis for the syndrome. @GENE$ and @GENE$ are both expressed in the hypothalamus and pituitary, and reduced expression or activity of PROKR2 is implicated in both Kallmann syndrome and PSIS, perhaps because of the important role this signaling pathway plays in endocrine angiogenesis and neuronal migration in this region of the central nervous system.",5505202,Prokineticin 2;9268,PROKR2;16368,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.A604T;tmVar:p|SUB|A|604|T;HGVS:p.A604T;VariantGroup:5;CorrespondingGene:2260;RS#:1412996644,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Protein structure analysis We performed protein structure analysis on the two @GENE$ mutations (@VARIANT$ and p.G213S) and two novel @GENE$ mutations (p.G257R and @VARIANT$) that were identified in this study.,3842385,WNT10A;22525,EDA;1896,p.R171C;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.I312M;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ @VARIANT$ and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A).",5887939,CELSR1;7665,DVL3;20928,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We identified four genetic variants (KCNQ1-p.R583H, @GENE$-p.C108Y, KCNH2-@VARIANT$, and @GENE$-@VARIANT$) in an LQTS family.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein. However, the two rare FUS variants (Y25C and @VARIANT$) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein.",6707335,SPG11;41614,ubiquilin-2;81830,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,P106L;tmVar:p|SUB|P|106|L;HGVS:p.P106L;VariantGroup:7;CorrespondingGene:2521;RS#:374191107;CA#:8023567,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (@VARIANT$).",3125325,USH2A;66151,CDH23;11142,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In our study, we identified four genetic variants in three genes (KCNQ1-@VARIANT$, KCNH2-p.C108Y, @GENE$-p.K897T, and @GENE$-@VARIANT$).",5578023,KCNH2;201,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Among the six variants (Table 2), two are missense variants in the @GENE$ (RBM43) gene (@VARIANT$) and the @GENE$ (DPT) gene (@VARIANT$).",5611365,RNA Binding Motif Protein 43;12715,dermatopontin;1458,p.V34L;tmVar:p|SUB|V|34|L;HGVS:p.V34L;VariantGroup:31;CorrespondingGene:375287;RS#:147060862;CA#:1902988,p.Y149C;tmVar:p|SUB|Y|149|C;HGVS:p.Y149C;VariantGroup:15;CorrespondingGene:1805;RS#:777651623;CA#:1231264,0
"To investigate possible oligogenic inheritance involving FOXC2 or @GENE$ and @GENE$, we also analyzed FOXC2 and PITX2 variants in a group of 25 CG cases who were known to carry CYP1B1 glaucoma-associated genotypes. The functional effect of three identified variants was assessed by transactivation luciferase reporter assays, protein stability and subcellular localization analyses. We found eight probands (6.0%) who carried four rare FOXC2 variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare PITX2 variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: @VARIANT$, p.(P179T)) have not been previously identified.",6338360,PITX2;55454,CYP1B1;68035,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
Causative heterozygous mutations in @GENE$ (@VARIANT$/c.1145A > G) and @GENE$ (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.,7026993,GFI1;3854,MYO6;56417,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,UNC13B;31376,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"@GENE$ plays a critical role in preventing aberrant mineralization but in order to be activated, this protein has to be fully carboxylated while under-carboxylated forms of the protein are inactive and can not prevent aberrant mineralization. In fact, skin biopsies from the proband and her sister depicted preponderance of under-carboxylated MGP, when examined by immunohistochemistry using specific antibodies that distinguish the fully carboxylated and under-carboxylated forms of the protein. Furthermore, assay of total ucMGP in plasma, which has been recently suggested to serve as a biomarker of cardiovascular calcification, was reduced in patients with skin findings, apparently reflecting tissue mineralization.   An intriguing observation in our family was the presence of PXE-like cutaneous features, with profound mineralization, in the proband's mother and aunt. These two individuals were heterozygous carriers of @VARIANT$ mutation in @GENE$ and @VARIANT$ in GGCX.",2900916,MGP;693,ABCC6;55559,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Two subjects (R302 and R462) had variants in genes involved in Ca 2+ regulation (RYR1 and CACNA1S), glycogen metabolism (GBE1 and PHKA1) and oxidative phosphorylation (@GENE$). Mutations in PHKA1 cause Glycogen Storage Disease type IX, X-linked phosphorylase kinase (PHK) enzyme deficiency, characterized by high muscle glycogen content and severe reduction of muscle @GENE$ activity. However, none of these signs were evident from metabolic work of the patient with PHKA1 @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and NDUFS8 I126V variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in RYR1 and CACNA1S are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects. Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the RYR1 @VARIANT$ variant in MH.",6072915,NDUFS8;1867,PHK;246,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,p.T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, @VARIANT$ in @GENE$, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and @GENE$ p.R408C with SETX p.I2547T and @GENE$ @VARIANT$).,4293318,TAF15;131088,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Of the 3 novel variants in DUOX2, @VARIANT$ was a frameshift mutation and had a potential deleterious effect on protein function and p.D137E and @VARIANT$ were missense mutations located in the peroxidase-like domain (Fig. S3A).  A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (SLC26A4, @GENE$, @GENE$ and TPO).",7248516,DUOX2;9689,DUOXA2;57037,p.T803fs;tmVar:p|FS|T|803||;HGVS:p.T803fsX;VariantGroup:61;CorrespondingGene:50506,p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991,0
"To the best of our knowledge, two of the identified variants (@GENE$: @VARIANT$, p.(H395N); and @GENE$: c.535C>A, @VARIANT$) have not been previously identified.",6338360,FOXC2;21091,PITX2;55454,c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/@GENE$-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (@GENE$ p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of @GENE$ (Supplemental Material, Fig. S3).",5966321,CELSR1;7665,PTK7;43672,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
"It could be argued that the TNFRSF13B/@GENE$ @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family. Hence, priority should be given to identifying the @GENE$ @VARIANT$ mutation for preimplantation genetic diagnosis and/or chorionic villus sampling.",5671988,TACI;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"C. Sanger sequencing confirmation of heterozygous @GENE$ variant @VARIANT$ (p.Gln247*) in V.5, and @GENE$ variant @VARIANT$ in VI.3.",6057824,COL4A1;20437,PKD2;20104,c.739C>T;tmVar:c|SUB|C|739|T;HGVS:c.739C>T;VariantGroup:0;CorrespondingGene:1282,c.715_718dupTACG;tmVar:c|DUP|715_718|TACG|;HGVS:c.715_718dupTACG;VariantGroup:2;CorrespondingGene:5311,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"PKD1 sequencing identified a likely pathogenic variant, p.(Asn2167Asp), absent in parents, and a second maternally inherited variant, p.(@VARIANT$). This is extremely rare (never reported before, absent in GnomAD), but with benign computational predictions, and it was classified as hypomorphic. We cannot formally test if variants in these two patients are in trans, but we presume they contributed to the severe clinical expression. In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2.",7224062,PKD1;250,PKD2;20104,Ala561Val;tmVar:p|SUB|A|561|V;HGVS:p.A561V;VariantGroup:10;CorrespondingGene:5311;RS#:542353495,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in @GENE$ were identified (online supplementary table S2). While TIMP3 blocks VEGF/VEGFR2 signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,TIMP3;36322,RASA1;2168,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0
Further segregation analyses of the two variants (p.R143W and @VARIANT$) among the six family members of SH60 as well as clinical evaluations including audiograms excluded both @VARIANT$ of @GENE$ and p.D771N of @GENE$ as a molecular etiology of SH60-136.,4998745,GJB2;2975,WFS1;4380,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,0
Mutations of @GENE$ and @GENE$ genes are closely related to LQTS. The mutations of KCNH2 @VARIANT$ and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,1
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in @GENE$ to block its activity in @GENE$/TGF-beta signalling.",6161649,SMAD1;21196,BMP;55955,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"In the subject III.1, the variant, carried in the heterozygous status, is the @VARIANT$; p.Glu290*, in the glucokinase (@GENE$) gene; the III.2 subject carried the @VARIANT$; p.Pro291Arg, in the @GENE$ gene.",8306687,CGK;55964,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"(A) MRI of a 31-year-old woman with compound heterozygous mutations in @GENE$, who received a diagnosis of polycystic kidneys at 17. (B) MRI of a 45-year-old woman, who carried two heterozygous variants in PKHD1, p.(@VARIANT$), and @GENE$, p.(@VARIANT$).",7224062,PKHD1;16336,PMM2;257,His3124Thr;tmVar:p|SUB|H|3124|T;HGVS:p.H3124T;VariantGroup:17;CorrespondingGene:5314,Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895,0
"The A194T substitution might cause conformational changes within the Cx31 molecule or affect the ability of @GENE$ to form heteromeric hemichannels. The relationship between hemichannel assembly may be complex, considering the different paradigms for connexin oligomerization. Many of the Cx26 mutant residues lie within the EC2 and TM4 domains. Mutations affecting these regions have also been reported in Cx32 underlying X-linked-Charcot-Marie-Tooth disease. Moreover, mutations in residues close to N166 and A194 identified in the families reported here, namely, M163L, @VARIANT$, F191L, and A197S in @GENE$ as well as F193C, S198F and @VARIANT$ in Cx32, have been reported previously in patients with hearing impairment.",2737700,Cx31;7338,Cx26;2975,R165W;tmVar:p|SUB|R|165|W;HGVS:p.R165W;VariantGroup:5;CorrespondingGene:2706;RS#:376898963;CA#:180672,G199R;tmVar:p|SUB|G|199|R;HGVS:p.G199R;VariantGroup:17;CorrespondingGene:2705,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin @VARIANT$, @GENE$ S166N, and pendrin @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (@VARIANT$) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b). These @GENE$ mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying @VARIANT$ of @GENE$ was previously reported.",7067772,EPHA2;20929,SLC26A4;20132,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the @GENE$ gene, both in heterozygous form.",6707335,CCNF;1335,ALS2;23264,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; p.L16V) and @GENE$ (c.9921T>G). Her father carries the mutations in @GENE$ and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,USH2A;66151,MYO7A;219,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,DCTN1;3011,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Moderate iodine deficiency in association with double heterozygosity for @GENE$ and DUOX2 mutations (S1 and parents) did not result in hypothyroidism (urinary iodine: mother 39.2 microg/L; father 38.7 microg/L; S1 43.1 microg/L; RR 100 to 700 microg/L) (Fig. 1). Discussion We report CH cases harboring a homozygous loss-of-function mutation in DUOX1 (@VARIANT$), inherited digenically with a homozygous @GENE$ nonsense mutation (@VARIANT$, p. R434*).",5587079,DUOX1;68136,DUOX2;9689,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,c.1300 C>T;tmVar:c|SUB|C|1300|T;HGVS:c.1300C>T;VariantGroup:0;CorrespondingGene:50506;RS#:119472026;CA#:116636,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"(D) The @GENE$ mutation @VARIANT$ and @GENE$ mutation @VARIANT$ were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"Interestingly, we unravel two novel missense mutations in @GENE$ (@VARIANT$) and @GENE$ (@VARIANT$) that are predicted to be damaging (Table 4).",5611365,OBSCN;70869,NFATC1;32336,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; @VARIANT$) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including @GENE$ may modulate the WS2 phenotype in WS2 cases with MITF mutation.",7877624,SNAI3;8500,LEF-1;7813,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, GRIN2A c.28C > A (@VARIANT$) and @GENE$ @VARIANT$ (p.Arg248Cys). The variant in @GENE$ was novel and was predicted to be damaging using both SIFT and PolyPhen.",7463850,PLXNB2;66630,GRIN2A;645,p.Leu10Met;tmVar:p|SUB|L|10|M;HGVS:p.L10M;VariantGroup:0;CorrespondingGene:2903,c.742C > T;tmVar:c|SUB|C|742|T;HGVS:c.742C>T;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0
"The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes.     ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The p.Ala349Thr (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of @GENE$ were detected.",3842385,EDA;1896,WNT10A;22525,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"  Digenic inheritances of GJB2/@GENE$ and GJB2/@GENE$ (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,MITF;4892,GJB3;7338,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"   Missense variants in the NEFH gene were detected in four patients: the T338I variant in two cases and the @VARIANT$ and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the GJB2/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, @VARIANT$) and one in @GENE$ (@VARIANT$, c.499G>C, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,p.Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,g.14574G>C;tmVar:g|SUB|G|14574|C;HGVS:g.14574G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue @GENE$ T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/@GENE$ C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of TCF3 and C104R (c.310T>C) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the TNFRSF13B/TACI @VARIANT$ mutation.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"RESULTS Mutations at the gap junction proteins @GENE$ and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,GJB6;4936,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"      WES revealed heterozygous mutations in two genes known to affect hypothalamic and pituitary development: c.253C>T;@VARIANT$ in @GENE$ (MIM 607123; NM_144773.2; rs141090506) inherited from an unaffected mother and c.1306A>G;@VARIANT$ in @GENE$ (MIM 606417; NM_018117.11; rs34602786) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1).",5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
"The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"This hypothesis was further supported when a patient with Kallmann syndrome was discovered to carry the same PROKR2 heterozygous mutation as our proband, @VARIANT$, in combination with a second heterozygous mutation in FGFR1, @VARIANT$;p.A604T (NM_023110.2), thereby providing evidence for a digenic basis for the syndrome. @GENE$ and PROKR2 are both expressed in the hypothalamus and pituitary, and reduced expression or activity of @GENE$ is implicated in both Kallmann syndrome and PSIS, perhaps because of the important role this signaling pathway plays in endocrine angiogenesis and neuronal migration in this region of the central nervous system.",5505202,Prokineticin 2;9268,PROKR2;16368,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1810G>A;tmVar:c|SUB|G|1810|A;HGVS:c.1810G>A;VariantGroup:5;CorrespondingGene:2260;RS#:1412996644,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; @VARIANT$) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, @GENE$, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and @GENE$) as well.",7877624,RNF43;37742,BCL9L;65615,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, @VARIANT$ in ISG20L2, rs143224912 in @GENE$ and @VARIANT$ in S100A3, and one novel variant in @GENE$, were identified.",6637284,SETDB1;32157,S100A13;7523,rs3795737;tmVar:rs3795737;VariantGroup:5;CorrespondingGene:81875;RS#:3795737,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of MSH6 @VARIANT$ protein. In addition, the genetic marker for MAP-tumors (@GENE$ @VARIANT$) was absent in this tumor, which points toward retained @GENE$ repair activity.",7689793,KRAS;37990,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.34G > T;tmVar:c|SUB|G|34|T;HGVS:c.34G>T;VariantGroup:12;CorrespondingGene:3845;RS#:587782084;CA#:13137,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The p.(@VARIANT$) mutation was predicted to be highly destabilizing. (C) Alignment of P4B3 domain (a.a. 1059-1097 of human LRP6). While @VARIANT$ is highly conserved among orthologs of @GENE$ and @GENE$, zebrafish LRP5 and Drosophila Arrow use threonine and aspartate, respectively, at this position.",8621929,LRP6;1747,LRP5;1746,Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,Asparagine1075;tmVar:p|Allele|N|1075;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,0
"To investigate possible oligogenic inheritance involving FOXC2 or @GENE$ and @GENE$, we also analyzed FOXC2 and PITX2 variants in a group of 25 CG cases who were known to carry CYP1B1 glaucoma-associated genotypes. The functional effect of three identified variants was assessed by transactivation luciferase reporter assays, protein stability and subcellular localization analyses. We found eight probands (6.0%) who carried four rare FOXC2 variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare PITX2 variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: c.535C>A, @VARIANT$) have not been previously identified.",6338360,PITX2;55454,CYP1B1;68035,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"  Considering the genotype/phenotype correlations, the proband and her sister were compound heterozygotes for both @GENE$ missense mutations, potentially explaining their hematologic findings. In addition, their skin findings resemble those recently reported by, in which 6 patients were demonstrated to have both coagulation factor deficiency and PXE-like skin changes due to mutations in the GGCX gene. In contrast, the proband's father, brother, her mother and maternal aunt were heterozygous for one of the GGCX mutations only, designating them as carriers without clinical hematologic findings. The latter individuals were also carriers of the ABCC6 nonsense mutation p.R1141X. It should be noted that the mother and her twin sister were heterozygous for one of the GGCX missense mutation @VARIANT$ and one ABCC6 nonsense mutation @VARIANT$, suggesting digenic inheritance of their cutaneous findings. The occurrence of digenic inheritance, although rare, is well established (see e.g.,). The chance of a combination of mutations in the @GENE$ and GGCX genes is difficult to calculate, since the precise carrier frequency of the mutations in these genes is not known.",2900916,GGCX;639,ABCC6;55559,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, @VARIANT$ and c.5749G>T in MYO7A, c.238_239dupC in USH1C, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for MYO7A, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for CDH23 , 11%-15% for PCDH15 , and for @GENE$ in USH2 patients, whereas the implication of VLGR1 and @GENE$ in the latter was minor.",3125325,USH2A;66151,WHRN;18739,c.3719G>A;tmVar:c|SUB|G|3719|A;HGVS:c.3719G>A;VariantGroup:87;CorrespondingGene:4647;RS#:542400234;CA#:5545997,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"    Family 4 with @GENE$ and @GENE$ mutations. (A) The pedigree indicates that the proband (II:1) was a simplex case of FTA. She was the only affected individual in the family. The DNA sequencing chromatograms from the proband show two LRP6 and one WNT10A heterozygous mutations. While both LRP6 variants, p.(Ser127Thr) and p.(@VARIANT$), were inherited from her father, the WNT10A mutation, @VARIANT$ was maternally derived.",8621929,LRP6;1747,WNT10A;22525,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.(Glu167Gln);tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in ENG by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,MAP4K4;7442,SCUBE2;36383,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CAPN11;21392,VPS13C;41188,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ @VARIANT$, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB p.G644V and @GENE$ @VARIANT$) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.K618R;tmVar:p|SUB|K|618|R;HGVS:p.K618R;VariantGroup:2;CorrespondingGene:5754;RS#:139041676,0
The c.229C>T (@VARIANT$) variant in @GENE$ and @VARIANT$ (p.I80Gfs*13) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2.,6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1
"The @GENE$ and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (c.229C>T, missense causing a @VARIANT$ mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,SETDB1;32157,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; @VARIANT$) and USH2A (@VARIANT$). Her father carries the mutations in MYO7A and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,USH1G;56113,USH2A;66151,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ p.P136L, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,DCTN1;3011,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type @GENE$ (Figure 4a), the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b). The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus lead to a reduction of structural stability. However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d).",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Similarly, SH170-377 carrying the @VARIANT$ mutation in GJB2 also contained a previously reported homozygous @VARIANT$*36 mutant allele in Myosin XVA (MYO15A) (NM_016239) (Table 1).       Although no other causative deafness mutation was detected in the initial analysis of TES data, Sanger sequencing for the low coverage area (<10x) in TES (see Table S2, Supplemental Content, which illustrates regions showing significantly low depth of coverage in TES: OTOF, @GENE$, and @GENE$) revealed the two known pathogenic STRC mutations as a compound heterozygous configuration in SB175-334 (Table 1).",4998745,STRC;15401,OTOA;71803,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.Glu396Argfs;tmVar:p|FS|E|396|R|;HGVS:p.E396RfsX;VariantGroup:15;CorrespondingGene:51168;RS#:772536599;CA#:8423043,0
"In the individual carrying the @VARIANT$ @GENE$ variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS.",6707335,NEFH;40755,GRN;1577,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
The @VARIANT$ (p.R77C) variant in @GENE$ and c.238-241delATTG (@VARIANT$) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2.,6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,1
"The @GENE$ @VARIANT$ variant is well described and classified as pathogenic in ClinVar and the Atlas of Cardiac Genetic Variation.                 4. Discussion Here we used targeted sequencing of 181 cardiomyopathy-related genes to identify the underlying genetic causes in three unrelated consanguineous families with DCM. We identified variants in two genes in family A. The first variant is p.Glu924Lys in MYH7, a well-documented missense variant that has been classified as pathogenic in its association with HCM and previously reported in the Atlas of Cardiac Genetic Variation and ClinVar. The second variant is a novel, missense variant in @GENE$ (@VARIANT$), not reported in control databases including gnomAD, GME Variome, and dbSNP.",6359299,MYH7;68044,LAMA4;37604,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,0
"Intriguingly, parents of the PCG-affected children who carried a single copy of the TEK or @GENE$ mutant allele were asymptomatic, suggesting that the heterozygous variations by themselves were not pathogenic.    Interaction of @GENE$ and CYP1B1 As the identified allelic combinations were extremely rare in our cohort, we carried out in vitro analysis to determine biochemical interaction between these proteins. First, we tested if TEK and CYP1B1 could physically interact with each other. Co-transfection of HEK293 (human embryonic kidney) cells with plasmids encoding recombinant HA-TEK (hemagglutinin-tagged TEK) and GFP-CYP1B1 followed by co-immunoprecipitation with anti-GFP-conjugated beads demonstrated that HA-TEK and GFP-CYP1B1 are part of the same complex. As negative control, no interaction was detected between the GFP tag and HA-TEK proteins (Fig. 2). Next, we asked whether the mutant combinations identified in patients can associate in the same assay. Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 @VARIANT$ to immunoprecipitate HA-TEK @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"In families F and K, a heterozygous missense mutation of a G-to-A transition at nucleotide 580 of @GENE$ that causes @VARIANT$, was found in profoundly deaf probands, who were also heterozygous for GJB2/@VARIANT$ (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the @GENE$/235delC was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Based on these findings, we conclude that, unlike LQTS-associated mutations, the @GENE$-@VARIANT$ variant does not severely affect the function of the channel. 2.3.2. KCNH2-p.C108Y Exhibits a Dominant-Negative Loss-of-Function Heterologous expression studies demonstrated that KCNH2-p.C108Y is a non-functional channel (Figure 4A). To evaluate if this mutant channel could exert a dominant negative effect, we recorded whole-cell currents in CHO-K1 cells co-expressing KCNH2-WT and KCNH2-p.C108Y. Cells co-expressing KCNH2-WT and @GENE$-@VARIANT$ had significantly lower activating and tail current densities at activating potentials between +20 and +60 mV compared to cells co-transfected with KCNH2-WT and an empty plasmid vector (Figure 4B,C).",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$).",5887939,DVL3;20928,SCRIB;44228,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"Furthermore, this @GENE$-@VARIANT$ mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (p.R1193Q, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in @GENE$ was also found in the proband (Fig 2D, Table 2). This SCN5A-@VARIANT$ variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and @GENE$ @VARIANT$ with @GENE$ p.I2547T and SETX @VARIANT$).,4293318,TAF15;131088,SETX;41003,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (LRP6 c.2450C>G, rs2302686), 0.0007 (@GENE$ @VARIANT$, rs761703397), and 0.0284 (@GENE$ c.637G>A, @VARIANT$) in EAS.",8621929,LRP6;1747,WNT10A;22525,c.4333A>G;tmVar:c|SUB|A|4333|G;HGVS:c.4333A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,rs147680216;tmVar:rs147680216;VariantGroup:7;CorrespondingGene:80326;RS#:147680216,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,MAP4K4;7442,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"However, none of these signs were evident from metabolic work of the patient with PHKA1 @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of @GENE$ D413N and @GENE$ @VARIANT$ variants remain unknown.",6072915,GBE1;129,NDUFS8;1867,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of @GENE$. Direct sequence analysis showing the 497A>G (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the @VARIANT$ (A194T) mutation (i and n) and WT allele (j and o) of @GENE$.   Expression of Cx31 and Cx26 in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against Cx26 (a) and Cx31 (b).,2737700,GJB2;2975,GJB3;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,580G>A;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants @VARIANT$; c.10384A>G), and 465F99 (rare @GENE$ missense variant @VARIANT$ and a novel @GENE$ missense variant c.10147G>A).",5887939,FZD1;20750,FAT4;14377,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and @GENE$ (@VARIANT$).",3125325,CDH23;11142,USH2A;66151,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in GAMT (NM_00156.4, c.79T>C, p.Tyr27His), @GENE$ (NM_018328.4, @VARIANT$, p.Leu667Trp), and @GENE$ (NM_004801.4, c.2686C>T, @VARIANT$), all of which were inherited.",6371743,MBD5;81861,NRXN1;21005,c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"Although @VARIANT$ did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a @GENE$ deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, FGF8, FGFR1, PROK2, PROKR2, @GENE$, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,KAL1;55445,TAC3;7560,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Two novel @GENE$ frameshift mutations were identified. A single-nucleotide duplication (@VARIANT$/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (@VARIANT$/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (c.1559G>A/p.Cys520Tyr) that cosegregated with both the AI phenotype and the ENAM mutation.",6785452,ENAM;9698,LAMA3;18279,c.395dupA;tmVar:c|DUP|395|A|;HGVS:c.395dupA;VariantGroup:18;CorrespondingGene:13801,c.2763delT;tmVar:c|DEL|2763|T;HGVS:c.2763delT;VariantGroup:0;CorrespondingGene:10117;RS#:529979202,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) GBE1 R524Ter; 2) PCCB G407RfrTer14; 3) @GENE$ IVS8DC; 4) OAT @VARIANT$. Two additional variants, p. T4823 M in @GENE$ and @VARIANT$ in CACNA1S, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,NUBPL;11854,RYR1;68069,"Y299Ter;tmVar:p|SUB|Y|299,ER|T;HGVS:p.Y299,ERT;VariantGroup:10;CorrespondingGene:4942",p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and @VARIANT$; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,ATP2A3;69131,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"GJB2 Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected @GENE$ Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (@VARIANT$) (rs121908073), and a novel variant, p.W482R of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,c.100C>T;tmVar:c|SUB|C|100|T;HGVS:c.100C>T;VariantGroup:11;CorrespondingGene:117531;RS#:121908073;CA#:253002,0
"Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,CAPN11;21392,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (c.2686C>T, @VARIANT$) and @GENE$ (c.3176G>A, @VARIANT$), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,p.Arg1059Gln;tmVar:p|SUB|R|1059|Q;HGVS:p.R1059Q;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"To the best of our knowledge, two of the identified variants (@GENE$: c.1183C>A, p.(H395N); and @GENE$: c.535C>A, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and p.(H395N); PITX2: @VARIANT$).",6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"There is a splicing site mutation @VARIANT$ in COL4A5, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (Gly1119Asp)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"DSCAML1 and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2).",6161649,DSCAM;74393,PTPN13;7909,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
"We found that @GENE$ variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants @VARIANT$ and @VARIANT$ activated the @GENE$ promoter similar to wt.",5893726,GATA4;1551,CYP17;73875,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,Pro226Leu;tmVar:p|SUB|P|226|L;HGVS:p.P226L;VariantGroup:1;CorrespondingGene:2626;RS#:368991748,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"So, we consider the patient to be the first reported case of @GENE$/@GENE$ digenic inheritance.     However, we should be aware of two limitations of MPS technology. First, the target region of MPS cannot cover all coding exons of USH genes. Actually, the coverage of the target exons was 97.0% in our study. So, it is impossible to detect a mutation in a region which is not covered using this system (Case #9: @VARIANT$). Secondarily, the MPS system used in this study, is not effective for detecting homo-polymer regions, for example poly C stretch (Case #8: @VARIANT$).",3949687,MYO7A;219,PCDH15;23401,c.5821-2A>G;tmVar:c|SUB|A|5821-2|G;HGVS:c.5821-2A>G;VariantGroup:42;CorrespondingGene:64072,p.Lys542GlnfsX5;tmVar:p|FS|K|542|Q|5;HGVS:p.K542QfsX5;VariantGroup:6;CorrespondingGene:4647;RS#:782077721;CA#:6197531,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"KCNH2 p.307_308del and @GENE$ @VARIANT$ of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A p.R1865H. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4). Compared with wild-type KCNH2 (Figure 4a), the structure of @GENE$ @VARIANT$ affected the single-stranded RNA folding, resulting in a false regional double helix (Figure 4b).",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and @VARIANT$; PITX2: @VARIANT$). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,1
"Her son, III.1, carrying the @GENE$ @VARIANT$ mutation only, also generated a similar proportion of IgG+ switched cells. However, individuals carrying the TNFRSF13B/@GENE$ @VARIANT$ mutation alone (II.3 and II.4) generated fewer IgG+ switched cells from naive cultures, even in the absence of TACI ligand engagement.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"We found eight probands (6.0%) who carried four rare @GENE$ variants in the heterozygous state. In addition, we found an elevated frequency (8%) of heterozygous and rare @GENE$ variants in the group of CG cases who were known to carry CYP1B1 glaucoma-associated genotypes, and one of these PITX2 variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: @VARIANT$, p.(P179T)) have not been previously identified.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"In families F and K, a heterozygous missense mutation of a @VARIANT$ of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively. In Family F, the @GENE$/@VARIANT$ was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f).",2737700,GJB3;7338,GJB2;2975,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The genotypes of @GENE$ (NM_001257180.2: c.1787A>G, @VARIANT$) and @GENE$ (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Patient P0418 carries a nonsense mutation in @GENE$ (@VARIANT$) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the @GENE$ mutation.",3125325,USH2A;66151,MYO7A;219,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, CELSR1 @VARIANT$ and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, @VARIANT$ located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of @GENE$ (Supplemental Material, Fig. S3).",5966321,SCRIB;44228,PTK7;43672,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0
"Coincidentally, PFBC patients with variants in both a PFBC pathogenic gene (@GENE$ or @GENE$) and another PFBC-unrelated gene (THAP1, CHRNB2, CASR, SCN2A or MEA6) were described as presenting more complex phenotypes, supporting the notion that a variant of a second gene may promote a heterogeneous phenotype in PFBC patients (Baker et al., 2014; Borges-Medeiros & de Oliveira, 2020; DeMeo et al., 2018; Fjaer et al., 2015; Fujioka et al., 2015; Knowles et al., 2018). The SLC20A2 c.1787A>G (@VARIANT$) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the PDGFRB c.317G>C (@VARIANT$) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
The @GENE$ gene [@VARIANT$; p.(Val114Leu)] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1).,8446458,DUSP6;55621,SEMA7A;2678,c.340G > T;tmVar:c|SUB|G|340|T;HGVS:c.340G>T;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,1
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in @GENE$ allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 3;7338,GJB2;2975,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/@GENE$-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"There is a splicing site mutation c.1339 + 3A>T in COL4A5, inherited from her mother and a missense mutation c.4421C > T (@VARIANT$) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,p. (Thr1474Met);tmVar:p|SUB|T|1474|M;HGVS:p.T1474M;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"In this family, the evidence-based on the genetic and functional findings indicated that the loss-of-function mutation CACNA1C-@VARIANT$ was the detrimental variation, and that the gain-of-function variant SCN5A-@VARIANT$ modulated the phenotype. The candidate genes of ERS included @GENE$ and @GENE$, which suggests that the interaction of variations in these 2 genes may potentially modify the penetrance of ERS phenotypes.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Under these conditions, co-expression of @GENE$ did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or @VARIANT$ (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and @GENE$ S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms.",7067772,EphA2;20929,pendrin;20132,Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
"Two of these variants were in genes implicated in heart development and cardiac pathology, @GENE$ and OBSCN (Table 4). The two variants chr18:77170979 G>A for NFATC1 and chr1:228462101 G>A for @GENE$ lead to novel missense variants, @VARIANT$ and @VARIANT$ respectively.",5611365,NFATC1;32336,OBSCN;70869,p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,LQT2;201,LQT6;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"A known pathogenic in-frame deletion @VARIANT$ (AF of 8.13180e-06_1000 Genomes) in exon1 of the MYD88 gene leading to absent protein expression resulting in a loss-of-function mutation, and a homozygous splice-donor variant @VARIANT$ (AF of G = 0.0008/4_1000 Genomes) in the @GENE$ gene, with absent protein, previously described as heterozygous variant. Sanger sequencing confirmed the mutations and both parents resulted heterozygous (data not shown). Since both mutated proteins caused impaired innate immunity we deeply investigated the myeloid compartment. Patient's monocytes showed a marked reduction of @GENE$-production (7-fold decreased) after LPS-stimulation (Figure 1E), although PB-monocytes (classical, intermediate, and non-classical), and major subtypes of dendritic cells (mDC1, mDC2, and pDC) were normally represented (data not shown).",6383679,CARD9;14150,TNFalpha;496,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"GJB2 Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected @GENE$ Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (rs121908073), and a novel variant, @VARIANT$ of @GENE$ (TMC1) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,Transmembrane channel-like 1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.W482R;tmVar:p|SUB|W|482|R;HGVS:p.W482R;VariantGroup:0;CorrespondingGene:117531;RS#:754142954;CA#:5081956,1
"@GENE$ mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of @GENE$ (@VARIANT$)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::@GENE$ (@VARIANT$) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Sequence alterations were detected in the COL6A3 (@VARIANT$), @GENE$ (rs143445685), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes.",6180278,RYR1;68069,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"The c.229C>T (@VARIANT$) variant in S100A3 and @VARIANT$ (p.I80Gfs*13) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.             Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, @GENE$ and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The absence of variant combinations involving the PROKR2 gene variant @VARIANT$ excludes its implication in digenic inheritance in the index case (HH12). Furthermore, since the variant is novel and has no functional evidence of pathogenicity, it is likely to be benign. Further molecular studies are needed to prove the deleterious character of the PROKR2 Lys205del variant. Except for the SEMA7A gene variant [p.(Glu436Lys)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)]. Such findings bring into question their involvement in disease expression in HH12. The SEMA7A variant [p.(Glu436Lys)] was predicted as VUS by Varsome. Sanger validation revealed the absence of this mutation in the healthy mother. The @GENE$ and @GENE$ genes were implicated in a digenic combination classified as ""dual molecular diagnosis"" by ORVAL.",8446458,SEMA7A;2678,DUSP6;55621,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"In Family F, the GJB2/@VARIANT$ was inherited from the unaffected father and the A194T of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the @VARIANT$/GJB3, while the mother is heterozygous for the @GENE$/299-300delAT (Fig. 1k).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The c.229C>T (@VARIANT$) variant in @GENE$ and @VARIANT$ (p.I80Gfs*13) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.             Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking S100A3, @GENE$ and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.",6637284,S100A3;2223,S100A13;7523,p.R77C;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (@GENE$ @VARIANT$). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,CCDC88C;18903,FGFR1;69065,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"We found that the p.I436V mutation, similar to other nearby amino acid substitutions that have been identified in individuals with idiopathic hypogonadotropic hypogonadism with and without anosmia, disrupted interaction of WDR11 with @GENE$. Specifically, heterozygous missense mutations in neighboring residues A435 (@VARIANT$;p.A435T; rs318240760) and R448 (c.1343G>A;p.R448Q; rs144440500) have been identified in each of two individuals with idiopathic hypogonadotropic hypogonadism and normosmia. In addition, in a different individual, the WDR11 p.A435T mutation was identified in association with a mutation in a second gene, @GENE$ (c.275T>C;@VARIANT$; MIM 138850; NM_000406.2), implicating digenic inheritance of this disorder as well.",5505202,EMX1;55799,GNRHR;350,c.1303G>A;tmVar:c|SUB|G|1303|A;HGVS:c.1303G>A;VariantGroup:0;CorrespondingGene:55717;RS#:318240760;CA#:130157,p.L92P;tmVar:p|SUB|L|92|P;HGVS:p.L92P;VariantGroup:8;CorrespondingGene:2629;RS#:1141815,0
"The @GENE$ and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both @VARIANT$ in S100A3 (c.229C>T, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,SETDB1;32157,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of @GENE$ and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,0
"Discussion We report CH cases harboring a homozygous loss-of-function mutation in @GENE$ (@VARIANT$), inherited digenically with a homozygous DUOX2 nonsense mutation (c.1300 C>T, @VARIANT$). The tertiary structure of @GENE$ is summarized in ; aberrant splicing of DUOX1 (c.1823-1G>C) will generate a truncated protein (p.Val607Aspfs*43) lacking the C-terminal flavin adenine dinucleotide and NADPH binding domains and cytosolic Ca2+ binding sites (EF-hand motifs) .",5587079,DUOX1;68136,DUOX1 and -2;53905;50506,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,p. R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and @GENE$ F355L mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
Her mother with @VARIANT$ in @GENE$ and her father with a missense mutation @VARIANT$ in @GENE$ had intermittent hematuria and proteinuria.,6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,1
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,ENG;92,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"In our study, we identified four genetic variants in three genes (@GENE$-p.R583H, KCNH2-p.C108Y, KCNH2-@VARIANT$, and @GENE$-@VARIANT$).",5578023,KCNQ1;85014,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,ubiquilin-2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Two different GJB3 mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of @GENE$ with @GENE$ is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (c.1514G>A, p.G505D). A novel missense mutation was found in @GENE$ (@VARIANT$, @VARIANT$).",6098846,TG;2430,DUOXA2;57037,c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$).",5887939,CELSR1;7665,DVL3;20928,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The genotypes of SLC20A2 (NM_001257180.2: c.1787A>G, @VARIANT$) and PDGFRB (NM_002609.4: @VARIANT$, p.Arg106Pro) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding @GENE$, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,ATP2A3;69131,VPS13C;41188,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,0
"On the contrary, the functionality of the @GENE$-@VARIANT$ channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, @GENE$-@VARIANT$, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,1
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Interestingly, four of these @GENE$ mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,1
"However, one of the patients heterozygous for the @VARIANT$ mutation in @GENE$ (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in KAL1 exon 8 (Figure S3), which was not detected in 500 alleles from control individuals. According to the predicted structure of @GENE$, the mutation modifies the first amino acid residue of the linker between the second and third fibronectin-like type III repeats, a residue that is conserved among orthologous proteins from vertebrates and invertebrates (Figure S3).",161730,PROKR2;16368,anosmin-1;55445,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (@GENE$). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (@GENE$)@VARIANT$, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,TACR3;824,DCC;21081,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Interestingly, the FTLD-TDP patient carrying the OPTN deletion is case B, who also carries the @GENE$ @VARIANT$ nonsense mutation, suggesting an oligogenic disease mechanism. Prompted by the idea of an oligogenic mechanism of disease we further looked at the presence of more frequent variants (MAF <0.1%) in individuals already harboring extremely rare variants in @GENE$ and TBK1 and noted that case A carrying the p.Gln235* nonsense variant in OPTN, is compound heterozygote for mutations in OPTN as it also carries the rare variant @VARIANT$ (NM_001008211.1:c.1442C>T) in OPTN (MAF=0.0116% in ESP - CADD_Phred score: 34).",4470809,TBK1;22742,OPTN;11085,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,p.Ala481Val;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas @GENE$-p.R583H, KCNH2-@VARIANT$, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"For example, patients 14 and 19 each carried one known truncating mutation (IVS28+1G>T) and a known inactivating mutation (@VARIANT$ or @VARIANT$). One showed severe CH and low intelligence level, and the other showed mild CH and normal intelligence. Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (p.R110Q or p.R885Q); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including @GENE$, @GENE$, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,TPO;461,TG;2430,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"In order to assess monogenic causes of early onset inflammatory colitis in this patient, we analyzed both subunits alpha and beta of the interleukin-10 receptor (@GENE$ and @GENE$), as well as nucleotide-binding oligomerization domain containing 2 (NOD2), since these genes are known to be associated with a higher risk for CD.  Results and Discussion Results We found 18 variants in our patient, five in the NOD2, four in the IL10RA and nine in the IL10RB genes. All variants localized respectively at the 5' and/or 3' untranslated, intronic and coding regions (Table 1). Among the variants identified in NOD2, four are known variants, and one, is a novel missense variant at the exon 9 (c.@VARIANT$ p.K953E) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of IL10RA, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.@VARIANT$ p.G351R), have already been described in the literature.",3975370,IL10RA;1196,IL10RB;523,2857A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,1051 G > A;tmVar:c|SUB|G|1051|A;HGVS:c.1051G>A;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Digenic Inheritance of @GENE$ and @GENE$ Mutations in Patient with Infantile Dilated Cardiomyopathy Background and objectives: Dilated cardiomyopathy (DCM) is a rare cardiac disease characterised by left ventricular enlargement, reduced left ventricular contractility, and impaired systolic function. Childhood DCM is clinically and genetically heterogenous and associated with mutations in over 100 genes. The aim of this study was to identify novel variations associated with infantile DCM. Materials and Methods: Targeted next generation sequencing (NGS) of 181 cardiomyopathy-related genes was performed in three unrelated consanguineous families from Saudi Arabia. Variants were confirmed and their frequency established in 50 known DCM cases and 80 clinically annotated healthy controls. Results: The three index cases presented between 7 and 10 months of age with severe DCM. In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in LAMA4 (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in MYH7 (c.2770G > A; @VARIANT$). The LAMA4 @VARIANT$ variant was predicted to be likely pathogenic according to international guidelines.",6359299,LAMA4;37604,MYH7;68044,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,0
"Mutation name is based on the full-length @GENE$ (NM_002960) and @GENE$ (NM_001024210) transcripts.    Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, rs143224912 in SETDB1 and rs138355706 in S100A3, and one novel variant in S100A13, were identified. The ISG20L2 and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,1
"Four genes (including AGXT2, @GENE$, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and @GENE$-c.1103C>T (@VARIANT$) were predicted to be causive by both strategies.",5725008,ZFHX3;21366,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,@GENE$,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,DNAH17;72102,CAPN11;21392,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Other family members who have inherited TCF3 @VARIANT$ and TNFRSF13B/TACI @VARIANT$ mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and C104R (c.310T>C) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and @VARIANT$ pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,FGFR1;69065,DCC;21081,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA.",7067772,pendrin;20132,EPHA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and @VARIANT$ (c.310T>C) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the TNFRSF13B/TACI C104R mutation.",5671988,TCF3;2408,TACI;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"This patient was subsequently found to carry a coexisting TIA1 variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same @GENE$ variant but a different @GENE$ mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,TIA1;20692,SQSTM1;31202,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,1
"      WES revealed heterozygous mutations in two genes known to affect hypothalamic and pituitary development: c.253C>T;@VARIANT$ in @GENE$ (MIM 607123; NM_144773.2; rs141090506) inherited from an unaffected mother and @VARIANT$;p.I436V in @GENE$ (MIM 606417; NM_018117.11; rs34602786) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1).",5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. @GENE$ @VARIANT$ was not internalized after ephrin-B2 stimulation while @GENE$ and other mutated pendrins were not affected.",7067772,Pendrin;20132,EphA2;20929,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the @GENE$ gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,KCNE2;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.",4470809,TBK1;22742,OPTN;11085,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).                   The @GENE$ variant [NM_033056: c.3101G > A; @VARIANT$] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892).",6053831,USH1G;56113,PCDH15;23401,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,p.(Arg1034His);tmVar:p|SUB|R|1034|H;HGVS:p.R1034H;VariantGroup:2;CorrespondingGene:124590,0
"Subsequently many genes encoding folate pathway enzymes, transporters and receptors have been studied with mostly inconsistent findings.7 More recently, several candidate variants were identified in @GENE$ and GLDC, 2 of the genes constituting the mitochondrial GCS.10, 32 In the present study, we identified a novel missense variant affecting the catalytic domain of the @GENE$ gene. This patient additionally carried the @VARIANT$ variant, and a rare missense variant (@VARIANT$) in the GLDC gene.",5887939,AMT;409,MTHFR;4349,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,c.2203G>T;tmVar:c|SUB|G|2203|T;HGVS:c.2203G>T;VariantGroup:3;CorrespondingGene:2731;RS#:143119940;CA#:4980332,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the 497A>G (@VARIANT$) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of Cx31 and Cx26 in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against @GENE$ (a) and @GENE$ (b).,2737700,Cx26;2975,Cx31;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in @GENE$. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles.",3125325,CDH23;11142,USH1G;56113,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (c.1062C > G; @VARIANT$); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution @VARIANT$ in @GENE$, leading to the change p.(Cys412Phe).",6567512,BBS7;12395,BBS6;10318,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,c.1235G > T;tmVar:c|SUB|G|1235|T;HGVS:c.1235G>T;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"The mutations of @GENE$ @VARIANT$ and @GENE$ p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous SCN5A @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (@VARIANT$;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus. Conclusions: WES in a child with PSIS and his unaffected family implicates a digenic mechanism of inheritance. In cases of hypopituitarism in which there is incomplete segregation of a monogenic genotype with the phenotype, the possibility that a second genetic locus is involved should be considered. A genetic cause was sought in a child with combined multiple pituitary hormone deficiencies. The findings implicate a digenic mechanism of inheritance, with a mutation in @GENE$ and in @GENE$. Pituitary stalk interruption syndrome (PSIS, ORPHA95496) is a congenital defect of the pituitary gland that is characterized by the triad of a very thin or interrupted pituitary stalk, an ectopic or absent posterior pituitary gland, and hypoplasia or aplasia of the anterior pituitary gland.",5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,1
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b). These @GENE$ mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying @VARIANT$ of @GENE$ was previously reported.",7067772,EPHA2;20929,SLC26A4;20132,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"In patient AVM226, we identified the compound heterozygous variants c.3775G>A (@VARIANT$) and c.2966A>T (p.Gln989Leu) in @GENE$ (table 2). DSCAML1 and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants c.116-1G>A and @VARIANT$ (p.Ser334Thr) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in @GENE$ to block its activity in BMP/TGF-beta signalling.",6161649,DSCAM;74393,SMAD1;21196,p.Val1259Ile;tmVar:p|SUB|V|1259|I;HGVS:p.V1259I;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: @VARIANT$ (p.G355R) and @GENE$: c.1229C>A (@VARIANT$), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1063G>A;tmVar:c|SUB|G|1063|A;HGVS:c.1063G>A;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"RESULTS Mutations at the gap junction proteins @GENE$ and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Sequencing of Case 7 revealed a heterozygous @VARIANT$ non-frameshift variation in exon 7 that leads to the deletion of amino acid 395 (p.Glu395del) in the LBD of the protein. This variant was also found in the mother of the patient. Except for Case 4, DNA samples of patients, in which only a single gene approach had been performed initially, were further analyzed by the targeted DSD gene panel including 48 genes. Additional heterozygous variants in known DSD genes were found in three out of six (50%) 46,XY DSD @GENE$ carriers. For Case 1, a novel missense VUS (variant of unknown significance) variant (c.361C>T; @VARIANT$) in the STAR gene was identified in the patient and his father. A rare variant in AMH, c.428C>T; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/@GENE$ (c.1632G>A; p.Met544Ile) pathogenic missense alteration was identified.",7696449,NR5A1;3638,FOG2;8008,c.1183_1185delGAG;tmVar:p|DEL|1183_1185|E;HGVS:p.1183_1185delE;VariantGroup:15;CorrespondingGene:1113,p.Arg121Trp;tmVar:p|SUB|R|121|W;HGVS:p.R121W;VariantGroup:7;CorrespondingGene:6770;RS#:34908868;CA#:4715265,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), @GENE$ (@VARIANT$), CAPN3 (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,RYR1;68069,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,UNC13B;31376,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, @VARIANT$ in @GENE$, rs143224912 in @GENE$ and @VARIANT$ in S100A3, and one novel variant in S100A13, were identified.",6637284,ISG20L2;12814,SETDB1;32157,rs3795737;tmVar:rs3795737;VariantGroup:5;CorrespondingGene:81875;RS#:3795737,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"This analysis indicated that the CAPN3 variant c.1663G>A (@VARIANT$), which results in a p.Val555Ile change, and the DES gene variant @VARIANT$ (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging. These 2 variants were further investigated employing the STRING program that analyzes protein networks and pathways. This analysis provided further support for our hypothesis that these mutations in the @GENE$ and @GENE$ genes, through digenic inheritance, are the cause of the myopathy in this patient.",6180278,CAPN3;52,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,c.656C>T;tmVar:c|SUB|C|656|T;HGVS:c.656C>T;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,1
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,ubiquilin-2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant.",8152424,CHD7;19067,FGFR1;69065,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; g.124339A>G, @VARIANT$, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,c.3224A>G;tmVar:c|SUB|A|3224|G;HGVS:c.3224A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"(a) Digenic inheritance of TNFRSF13B (@VARIANT$, C104R TACI) and TCF3 (T168fx191) mutations in a three-generation New Zealand family. Whole-exome sequencing was performed on II.2, III.1 and III.2 (indicated by *). The proband (II.2) is indicated by an arrow. Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue TCF3 T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and @GENE$/TACI C104R mutations.",5671988,TCF3;2408,TNFRSF13B;49320,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Mutations in melanocyte inducing transcription factor (@GENE$), coding for a basic helix-loop-helix (BHLH) leucine zipper protein, are known to cause the WS2 phenotype due to defects in survival, proliferation, and migration of melanocytes. The deletion mutation (c.965delA) identified in this study lies in the BHLH domain and predicted to cause frameshift (@VARIANT$) and stop codon seven amino acids downstream (Asn322Metfs*7). The missense variant (@VARIANT$) in the @GENE$ gene changes the conserved amino acid Valine to Glycine (p.Val34Gly).",7877624,MITF;4892,C2orf74;49849,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,GJB6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"RNA secondary structure of @GENE$ @VARIANT$ showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the @GENE$ protein property, SCN5A @VARIANT$ slightly increased the molecular weight and aliphatic index but reduced the instability index.",8739608,KCNH2;201,Nav1.5;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"For example, two variants in proband P15, @VARIANT$ in @GENE$ and @VARIANT$ in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother.",8152424,PROKR2;16368,DCAF17;65979,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,1
"Four genes (including AGXT2, ZFHX3, SCAP, @GENE$) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and @GENE$-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,TCF4;2407,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (@VARIANT$), SNAI2 (@VARIANT$) and @GENE$ (c.101T>G) genes. Variant in @GENE$ is not segregating with the disease phenotype therefore it was excluded as an underlying cause of WS2 in the family.",7877624,C2orf74;49849,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in @GENE$. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain.",4470809,OPTN;11085,TBK1;22742,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"p.R1110Q was the most common mutation identified in our patient cohort, which differed from previous reports in Korean (p.G488R) and Japanese (@VARIANT$) populations. Additionally, p.K530X was the most common mutation identified in Chinese patients from southern or central China. Besides DUOX2, TG anomalies are another common cause of DH. However, in the present study, four detected @GENE$ variants presented separately in four different patients with heterozygosity and always cooccurred with variants in DUOX2 or other DH-related genes, indicating that the contributions of TG mutations to DH in Xinjiang Han Chinese might be less important. More CH-associated @GENE$ mutations were found recently. Our study identified two known truncating variants, p.Y246X and p.Y138X, which cooccurred in a patient with permanent CH. A previous study first noted p.Y246X homozygosity in a patient with mild permanent CH and dyshormonogenic goiter, and compound heterozygosity with p.Y138X and @VARIANT$ was reported in another patient.",6098846,TG;2430,DUOXA2;57037,p.R855Q;tmVar:p|SUB|R|855|Q;HGVS:p.R855Q;VariantGroup:45;CorrespondingGene:50506,p.Y246X;tmVar:p|SUB|Y|246|X;HGVS:p.Y246X;VariantGroup:8;CorrespondingGene:90527;RS#:4774518;CA#:114294,0
"The patient carried a heterozygous variant of unknown significance in @GENE$, p.(@VARIANT$), defined as likely pathogenic in ClinVar, and a missense variant p.(@VARIANT$) in PMM2, classified as likely pathogenic. Recessive mutations in @GENE$ were reported as associated to hyperinsulinemic hypoglycemia (HI) and PKD (Cabezas et al.,).",7224062,PKHD1;16336,PMM2;257,His3124Tyr;tmVar:p|SUB|H|3124|Y;HGVS:p.H3124Y;VariantGroup:17;CorrespondingGene:5314,Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,ANG;74385,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,TACR3;824,NELF;10648,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Proband 17 inherited CHD7 @VARIANT$ and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,CDON;22996,CCDC88C;18903,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (@VARIANT$) mutation in @GENE$ were detected.,3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 @VARIANT$ (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and SCN5A @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"  To gain further insight into the role of EphA2 on @GENE$ regulation, pendrin A372V, L445W, @VARIANT$ or G672E was co-overexpressed with @GENE$. The cells were transfected with cDNAs of encoding myc-pendrin diease forms with that of EphA2, and the non-permeable cells were stained with an anti-myc antibody. While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, Q446R, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, EphA2 overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,pendrin;20132,EphA2;20929,Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,VAPB;36163,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Note that subject II:1 in family PCG-133 was diagnosed at the age of 3 months and carried the de novo @VARIANT$ PITX2 variant, whereas his brother, who did not carry this variant, was diagnosed at the age of 10 years. The proband in family PCG-139 also carried a rare PITX2 variant (@VARIANT$) and presented glaucoma diagnosed at the age of seven days. Both probands required more surgical operations to control IOP than the rest of patients. Below symbols are indicated genotypes for @GENE$ and @GENE$, age at diagnosis and number or surgical operations per eye, respectively.",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (c.253C>T;@VARIANT$) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant @GENE$ loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus.",5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,GJB3;7338,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (@VARIANT$) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-@GENE$ E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-@GENE$ R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and @VARIANT$ exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 @VARIANT$ and R368H showed perturbed interaction with HA-TEK.",5953556,TEK;397,CYP1B1;68035,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,@GENE$,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,CAPN11;21392,VPS13C;41188,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Quantification of cells with dilated endoplasmic reticulum (ER) and COPII vesicles associated with Golgi by transmission electron microscopy Genotype of cell line Cells with dilated ER (%) Cells with Golgi-associated vesicles (%) Wt (N = 414) 2 (0.5) 309 (75) SEC23Ac.1200G>C/+ (N = 83) 83 (100***) 9 (11***) SEC23Ac.@VARIANT$/+ MAN1B1c.1000C>T/+ (N = 190) 190 (100***) 3 (1.6***) SEC23Ac.1200G>C/c.1200G>C; MAN1B1c.1000C>T/@VARIANT$ (N = 328) 328 (100***) 2 (0.6***)  Increased Intracellular and Secreted Pro-COL1A1 in Fibroblasts with Homozygous Mutations in Both @GENE$ and @GENE$ in the Presence of l-Ascorbic Acid SEC23A is required for normal transport of pro-COL1A1, a major extracellular matrix component of bone.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Notably, the patients carrying the p.T688A and @VARIANT$ mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, @VARIANT$, p.R268C (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, PROKR2, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROK2;9268,p.I400V;tmVar:p|SUB|I|400|V;HGVS:p.I400V;VariantGroup:3;CorrespondingGene:10371;RS#:36026860;CA#:220071,p.Y217D;tmVar:p|SUB|Y|217|D;HGVS:p.Y217D;VariantGroup:13;CorrespondingGene:3730,0
"A single control also had two mutations, @VARIANT$ in ALS2 and @VARIANT$ in @GENE$. ALS2 pathogenicity has only been observed in homozygotes, and this individual was heterozygous. Furthermore, the TARDBP variant has been previously identified in controls and has unclear status, although it is associated with abnormal localization and aggregation of TARDBP. What constitutes a pathogenic combination of mutations is debatable as some variants are of uncertain significance, and the combination of a pathogenic variant with one of uncertain significance has been considered oligogenic inheritance by some. Similarly, variation in ANG or NEFH is generally considered a weak contributor to ALS risk, and missense variants in SPG11 are often benign unless resulting in loss of function. We find oligogenic inheritance even when these genes are excluded from the analysis. Notably, one of our controls harboured a loss-of-function mutation in @GENE$. Allowing a looser definition of oligogenic inheritance, oligogenic ALS is reported in ~1.6% of cases (4% in familial and 1.3% in sporadic ALS).",5445258,TARDBP;7221,SPG11;41614,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0
"(E) The EDA mutation @VARIANT$ and @GENE$ mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations c.1045G>A in @GENE$ and c.511C>T in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,WNT10A;22525,EDA;1896,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"(E) The @GENE$ mutation c.466C>T and @GENE$ mutation c.637G>A were found in patient S3, who inherited the mutant allele from his mother. (F) The mutations @VARIANT$ in EDA and @VARIANT$ in WNT10A were found in patient S4, but his mother's DNA sample could not be obtained.",3842385,EDA;1896,WNT10A;22525,c.1045G>A;tmVar:c|SUB|G|1045|A;HGVS:c.1045G>A;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene @GENE$ were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"In patient AVM558, the de novo heterozygous missense variant @VARIANT$ (p.Arg565Gln) was identified in MAP4K4 (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within @GENE$, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant @VARIANT$ (p.Asn692Ser) was identified in CDH2 (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions. N-cadherin mediates brain angiogenesis by stabilising angiogenic capillaries, possibly by enhancing the interaction between pericytes and endothelial cells. At the molecular level, N-cadherin mediates cell-cell adhesion by regulating PI3K/Akt signalling (figure 3).      In patient AVM467, the de novo heterozygous missense variant c.676G>A (p.Gly226Ser) was identified in @GENE$ (table 1).",6161649,SMAD1;21196,IL17RD;9717,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,c.2075A>G;tmVar:c|SUB|A|2075|G;HGVS:c.2075A>G;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), @GENE$ p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD @VARIANT$ (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and @GENE$ genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous SCN5A @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,LAMA2;37306,SCN5A;22738,p.E1028V;tmVar:p|SUB|E|1028|V;HGVS:p.E1028V;VariantGroup:5;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"4.4. Cell Culture and Heterologous Expression Chinese hamster ovaries (CHO-K1, American Type Culture Collection) were grown in F-12 HAM nutrient mixture medium (11765-054, ThermoFischer Scientific Inc., Waltham, MA, USA) supplemented with 10% fetal bovine serum (ThermoFisher Scientific Inc., Waltham, MA, USA), 2 mM l-glutamine, 50 U/mL penicillin, and 50 mug/mL streptomycin (Sigma, St. Louis, MO, USA) in a humidified 5% CO2 atmosphere at 37  C. Cells were transfected using Fugene 6 (Roche, Mannheim, Germany) in 21 cm2 dishes with 1 mug (@GENE$-WT or KCNQ1-@VARIANT$) or 1.5 mug (KCNH2-WT or @GENE$-@VARIANT$) plasmid/dish in transient transfection experiments.",5578023,KCNQ1;85014,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,0
"Hence, priority should be given to identifying the @GENE$ @VARIANT$ mutation for preimplantation genetic diagnosis and/or chorionic villus sampling. Based on both clinical and laboratory quantification, it appears neither the @GENE$/TACI @VARIANT$ mutation nor the TCF3 T168fsX191 mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"c, d Immunoprecipitation of @GENE$ with mutated pendrin. Immunocomplex of myc-@GENE$ @VARIANT$, S166N and @VARIANT$ was not affected.",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and @GENE$ c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$).",5887939,CELSR1;7665,DVL3;20928,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and @VARIANT$ (c.310T>C) mutation of @GENE$ gene in the proband II.2.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Human placental JEG3 cells were transfected with a CYP17-promoter luciferase reporter construct, and the activity of wild-type (wt) and mutant @GENE$ to trans-activate the promoter was tested using the Promega Dual Luciferase readout system. Results are shown as the mean +- SEM of four independent experiments, all performed in duplicate. **p-Value <= 0.01.          In Silico GATA4 Protein Structure-Function Analysis Using the structures of GATA1 and @GENE$ available in the protein structure database, we created a protein structure model of GATA4. GATA4 was modeled with dual zinc atoms, which were coordinated with cysteines (Figure 4). One Zn atom is bound to cysteines 217, 220, 238, and 241, while the second Zn atom is bound to cysteines 272, 275, 293, and 296. Mutation of any of these cysteine molecules as well as neighboring residues is expected to result in loss of Zn binding. Among the mutations studied in this report, we found the mutations @VARIANT$ and Cys238Arg to cause loss of Zn binding leading to an unstable protein with predicted loss of function (Figure 4). The mutations Pro226Leu and @VARIANT$ are involved in interaction with DNA and their effects were predicted to be variable.",5893726,GATA4;1551,GATA3;1550,Gly221Arg;tmVar:p|SUB|G|221|R;HGVS:p.G221R;VariantGroup:4;CorrespondingGene:2626;RS#:398122402(Expired),Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ A115P and GFP-CYP1B1 @VARIANT$ to immunoprecipitate HA-@GENE$ E103D and HA-TEK @VARIANT$, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 @VARIANT$, @GENE$ @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"Among the 8 novel variants, 4 were classified as P (@VARIANT$ and p.K618* in @GENE$, p.T803fs in DUOX2) or LP (@VARIANT$ in @GENE$), the other were classified as VUS.",7248516,TSHR;315,DUOX2;9689,p.C176R;tmVar:p|SUB|C|176|R;HGVS:p.C176R;VariantGroup:32;CorrespondingGene:7038;RS#:200511116,p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506,0
"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, @GENE$ c.1200G>C (@VARIANT$) and @GENE$ @VARIANT$ (p.R334C), associated with congenital birth defects in two patients from a consanguineous family.",4853519,SEC23A;4642,MAN1B1;5230,p.M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1
"To the best of our knowledge, two of the identified variants (@GENE$: @VARIANT$, p.(H395N); and @GENE$: @VARIANT$, p.(P179T)) have not been previously identified.",6338360,FOXC2;21091,PITX2;55454,c.1183C>A;tmVar:c|SUB|C|1183|A;HGVS:c.1183C>A;VariantGroup:8;CorrespondingGene:2303,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:@VARIANT$; @VARIANT$) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"In addition, 2 genes presented variants in 3 patients: MAML3 (patients 6, 7 and 8) and @GENE$ (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and @GENE$ variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,NOTCH1;32049,MAML3;41284,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Except for the SEMA7A gene variant [p.(Glu436Lys)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the @GENE$ gene variant [p.(@VARIANT$)]. Such findings bring into question their involvement in disease expression in HH12. The @GENE$ variant [p.(@VARIANT$)] was predicted as VUS by Varsome.",8446458,DUSP6;55621,SEMA7A;2678,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"It was shown that digenic variants in CYP1B1 and MYOC contribute to PCG and that variants in both @GENE$ and @GENE$ are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, @VARIANT$, p.L86F, @VARIANT$, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,FOXC1;20373,PITX2;55454,p. A85P;tmVar:p|SUB|A|85|P;HGVS:p.A85P;VariantGroup:78;CorrespondingGene:6012,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and @VARIANT$ (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,MAP4K4;7442,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.1000T>A;tmVar:c|SUB|T|1000|A;HGVS:c.1000T>A;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"The @VARIANT$ mutation in MAN1B1 was previously shown to result in decreased MAN1B1 protein levels and to encode for an enzyme with reduced catalytic function. also showed that patients with this mutation had abnormal N-glycan remodeling. Our data are consistent with those of Rafiq et al. and Rymen et al., as we found reduced MAN1B1 protein levels and glycosylation defects in patients double homozygous for the 1000C>T @GENE$ and the @VARIANT$ @GENE$ mutations.",4853519,MAN1B1;5230,SEC23A;4642,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,12000 G>C;tmVar:g|SUB|G|12000|C;HGVS:g.12000G>C;VariantGroup:14;CorrespondingGene:10484,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, @VARIANT$), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,TOR2A;25260,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"On the contrary, the functionality of the @GENE$-@VARIANT$ channels was not severely compromised in a manner typical of LQTS-associated mutations. Our study suggests that the KCNH2-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-p.C108Y homozygous tetramers and KCNH2-WT/@GENE$-@VARIANT$ heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, @VARIANT$, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.494C>T;tmVar:c|SUB|C|494|T;HGVS:c.494C>T;VariantGroup:185;CorrespondingGene:4647;RS#:111033174;CA#:278676,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys.",3842385,WNT10A;22525,EDA;1896,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, @VARIANT$ and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,c.475A > G;tmVar:c|SUB|A|475|G;HGVS:c.475A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different @GENE$ mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,TIA1;20692,SQSTM1;31202,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, @GENE$ p.R769W, DVL3 @VARIANT$, PTK7 @VARIANT$, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and CYP1B1 proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins @VARIANT$ and I148T exhibited diminished interaction with wild-type GFP-@GENE$. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-TEK. The residues E103, I148, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d). This suggested that either the N-terminal @GENE$ domain was involved in the interaction with CYP1B1 or that the mutations altered the conformation of the TEK protein, which affected a secondary CYP1B1-binding site.",5953556,CYP1B1;68035,TEK;397,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous @VARIANT$ in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,gap junction protein beta 2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"Sequence alterations were detected in the @GENE$ (rs144651558), RYR1 (@VARIANT$), @GENE$ (@VARIANT$), and DES (rs144901249) genes.",6180278,COL6A3;37917,CAPN3;52,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"Furthermore, this @GENE$-@VARIANT$ mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (p.R1193Q, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This @GENE$-@VARIANT$ variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"Notably, proband P05 in family 05 harbored a de novo @GENE$ @VARIANT$ variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).",8152424,FGFR1;69065,CCDC88C;18903,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,1
"Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (@VARIANT$) mutation was also detected in exon 3 of WNT10A, it results in the substitution of Gly at residue 213 to Ser.",3842385,WNT10A;22525,EDA;1896,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI3;8500,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,1
"In patient AVM359, one heterozygous VUS (@VARIANT$ [p.Arg197Trp]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling.",6161649,ENG;92,SCUBE2;36383,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0
"Additionally, @VARIANT$ was the most common mutation identified in Chinese patients from southern or central China. Besides @GENE$, TG anomalies are another common cause of DH. However, in the present study, four detected @GENE$ variants presented separately in four different patients with heterozygosity and always cooccurred with variants in DUOX2 or other DH-related genes, indicating that the contributions of TG mutations to DH in Xinjiang Han Chinese might be less important. More CH-associated DUOXA2 mutations were found recently. Our study identified two known truncating variants, p.Y246X and p.Y138X, which cooccurred in a patient with permanent CH. A previous study first noted p.Y246X homozygosity in a patient with mild permanent CH and dyshormonogenic goiter, and compound heterozygosity with p.Y138X and p.Y246X was reported in another patient. These cases were of Chinese origin, suggesting that @VARIANT$ and p.Y138X are specific pathogenic variants in Chinese populations.",6098846,DUOX2;9689,TG;2430,p.K530X;tmVar:p|SUB|K|530|X;HGVS:p.K530X;VariantGroup:6;CorrespondingGene:50506;RS#:180671269;CA#:7538552,p.Y246X;tmVar:p|SUB|Y|246|X;HGVS:p.Y246X;VariantGroup:8;CorrespondingGene:90527;RS#:4774518;CA#:114294,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
A male (ID104) was found to have a heterozygous missense variant c.989A > T (@VARIANT$) in @GENE$ and a missense variant c.1777C > G (@VARIANT$) in @GENE$. Limited clinical information was available about this male.,7463850,EHMT1;11698,SLC9A6;55971,p.Lys330Met;tmVar:p|SUB|K|330|M;HGVS:p.K330M;VariantGroup:1;CorrespondingGene:79813;RS#:764291502,p.Leu593Val;tmVar:p|SUB|L|593|V;HGVS:p.L593V;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,1
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"In patient AVM359, one heterozygous VUS (@VARIANT$ [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,c.589C>T;tmVar:c|SUB|C|589|T;HGVS:c.589C>T;VariantGroup:2;CorrespondingGene:83394;RS#:2229778;CA#:2061380,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,0
"Notably, the common variants @GENE$-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNE1;3753,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (@VARIANT$, p.E229K, and p.R368H) in five families.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"          Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/@GENE$ regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, @VARIANT$, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-@GENE$ @VARIANT$, S166N and F355L was not affected.",7067772,ephrin-B2;3019,pendrin;20132,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
"The heterozygous SCN5A@VARIANT$ was carried by her father and sister but not carried by I:2. II:1 carried with KCNH2 @VARIANT$ as a de novo mutation, but not existed in other family members. RNA secondary structure of @GENE$ p.307_308del showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Nav1.5 protein property, SCN5A p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index.   Conclusions The digenic heterozygous KCNH2 and SCN5A mutations were associated with young early-onset long QT syndrome and sinoatrial node dysfunction.   Abbreviations ARVC/D arrhythmogenic right ventricular cardiomyopathy/dysplasia ECG electrocardiogram ICD implantable cardioverter-defibrillator   KCNH2 known as KV11.1, delayed rectifier K+ channels LQTS long QT syndrome SCD sudden cardiac death @GENE$A known as Nav1.5, cardiac-type voltage-dependent Na+ channel     WES whole-exome sequencing   INTRODUCTION Long QT syndrome (LQTS) is an inherited cardiac electrophysiologic disorder characterized by QT interval prolongation in the electrocardiogram and family history of sudden cardiac death (SCD) (Neira et al.,; Wallace et al.,).",8739608,KCNH2;201,SCN5;5250,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"@GENE$ gene might interact with MITF gene product and give rise to the spectrum of phenotype varying from severe phenotype with complete penetrance to partial features. Conclusion In this study, we analysed a large family segregating Waardenburg syndrome type 2 to identify the underlying genetic defects. Whole genome SNP genotyping, whole exome sequencing and segregation analysis using Sanger approach was performed and a novel single nucleotide deletion mutation (@VARIANT$) in the @GENE$ gene and a rare heterozygous, missense damaging variant (c.101T>G; @VARIANT$) in the C2orf74 was identified.",7877624,C2orf74;49849,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Val34Gly;tmVar:p|SUB|V|34|G;HGVS:p.V34G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel @VARIANT$ variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form.",6707335,GRN;1577,SIGMAR1;39965,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"    Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation c.936C>G and WNT10A mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Hence, priority should be given to identifying the @GENE$ T168fsX191 mutation for preimplantation genetic diagnosis and/or chorionic villus sampling. Based on both clinical and laboratory quantification, it appears neither the @GENE$/TACI @VARIANT$ mutation nor the TCF3 @VARIANT$ mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband.",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 @VARIANT$ variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"A single-nucleotide duplication (@VARIANT$/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (@VARIANT$/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide @GENE$ deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (c.1559G>A/p.Cys520Tyr) that cosegregated with both the AI phenotype and the ENAM mutation.",6785452,ENAM;9698,LAMA3;18279,c.395dupA;tmVar:c|DUP|395|A|;HGVS:c.395dupA;VariantGroup:18;CorrespondingGene:13801,c.2763delT;tmVar:c|DEL|2763|T;HGVS:c.2763delT;VariantGroup:0;CorrespondingGene:10117;RS#:529979202,0
"For Case 1, a novel missense VUS (variant of unknown significance) variant (@VARIANT$; p.Arg121Trp) in the @GENE$ gene was identified in the patient and his father. A rare variant in AMH, c.428C>T; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/@GENE$ (@VARIANT$; p.Met544Ile) pathogenic missense alteration was identified.",7696449,STAR;297,FOG2;8008,c.361C>T;tmVar:c|SUB|C|361|T;HGVS:c.361C>T;VariantGroup:7;CorrespondingGene:6770;RS#:34908868;CA#:4715265,c.1632G>A;tmVar:c|SUB|G|1632|A;HGVS:c.1632G>A;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"SCN5A p.R1865 and KCNH2 p.307_308 of amino acid sequences were highly conserved across the common species Sanger sequencing for @GENE$ and @GENE$ mutations. KCNH2 @VARIANT$ and SCN5A p.R1865H of the proband were validated as positive by Sanger sequencing. Additionally, I: 1 and II: 2 carried with the heterozygous for SCN5A @VARIANT$. Except II: 1, other family members did not carry with the KCNH2 mutation   RNA secondary structure prediction The RNA secondary structure differences were presented by the RNAfold WebSever (Figure 4).",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"KAT2B @VARIANT$ but not @GENE$ E659Q causes cardiac defects in Drosophila Since the presence of SRNS and heart defects in family A was the main phenotypic difference from the other families, we looked more specifically into the cardiac and renal system of the fly. The Drosophila heart is a tubular organ formed by contractile cardiomyocytes that pump the hemolymph (analogous to the blood in vertebrates) to the rest of the body. This organ system has proven to be an important tool for studying the genetics and pathophysiology of cardiac disease. Therefore, we studied heart function in adult adducin and Gcn5 rescue flies. As illustrated in the M-mode traces obtained from high-speed movies, @GENE$-alphagamma @VARIANT$ did not show any significant differences in heart period, cardiac output, fractional shortening and arrhythmia index when compared to adducin-alphagamma WT (Fig 4).",5973622,ADD3;40893,adducin;22758,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,0
"We report digenic variants in @GENE$ and @GENE$ associated with NTDs in addition to SCRIB and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,PTK7;43672,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Genetic diagnosis was obtained in 12/20 patients using a NGS targeted approach analysing simultaneously the 18 most frequently mutated genes associated with BBS to increase the detection rate and the understanding of the @GENE$ phenotype through discovery of additional mutations in BBS genes that could explain differences in phenotype severity. The study revealed @GENE$ gene mutations in a majority of our cohort (33%), in accordance with the percentages already reported in the literature. Interestingly, we found just one patient with variants in BBS1, the most frequently detected gene in BBS patients. We identified a novel variant in BBS1 patient #10 c.1285dup (p.(Arg429Profs*72)) defined as pathogenic that segregates with phenotype together with c.46A > T (p.(Ser16Cys), defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, @VARIANT$, was identified in patient #3.",6567512,BBS;12122,BBS10;49781,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo @GENE$ p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,FUS;2521,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"The genotypes of SLC20A2 (NM_001257180.2: c.1787A>G, @VARIANT$) and PDGFRB (NM_002609.4: c.317G>C, @VARIANT$) for available individuals are shown. Regarding @GENE$, A/G = heterozygous mutation carrier, and A/A = wild type; regarding @GENE$, G/C = heterozygous mutation carrier, and G/G = wild type.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Moreover, the MAF of KCNQ1-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of @GENE$-p.K897T and @GENE$-p.G38S were much larger (0.187 and 0.352, respectively). KCNH2-p.@VARIANT$ is not reported in the ExAC database.",5578023,KCNH2;201,KCNE1;3753,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, @VARIANT$ in USH1C, and @VARIANT$ and c.10712C>T in USH2A. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance. Previous mutation research studies performed in patients referred to medical genetic clinics showed high proportions of mutations for @GENE$, CDH23 and PCDH15 in USH1 patients, specifically, 29%-55% for MYO7A , 19%-35% for CDH23 , 11%-15% for @GENE$ , and for USH2A in USH2 patients, whereas the implication of VLGR1 and WHRN in the latter was minor.",3125325,MYO7A;219,PCDH15;23401,c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Sequence alterations were detected in the COL6A3 (rs144651558), @GENE$ (rs143445685), CAPN3 (@VARIANT$), and @GENE$ (@VARIANT$) genes.",6180278,RYR1;68069,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,SPTBN4;11879,MYOD1;7857,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,0
"    Sequence analyses of @GENE$ and @GENE$ genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"The @VARIANT$ residue of @GENE$ is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/MITF and @GENE$/GJB3 (group II). (A) In addition to c.235delC in GJB2, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3.",4998745,MITF;4892,GJB2;2975,p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C @VARIANT$). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,DCC;21081,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Our study suggests that the @GENE$-p.C108Y variant has pathogenic properties consistent with LQTS. KCNH2-@VARIANT$ homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in @GENE$ (@VARIANT$/c.1145A > G) and MYO6 (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,MYO6;56417,GFI1;3854,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"Moreover, mutations in residues close to @VARIANT$ and A194 identified in the families reported here, namely, M163L, R165W, F191L, and A197S in Cx26 as well as F193C, S198F and @VARIANT$ in @GENE$, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the Cx31 gene except for the EC2 and TM4 domains, which are main domains for deafness mutations. This correlation between location of mutations and phenotypes, together with the identification of pathological mutations associated with hearing loss in the same region of the EC2 and TM4 domains in these three connexin genes (Cx26, Cx31, and Cx32) suggested that the EC2 and TM4 domains are important to the function of the @GENE$ protein in the inner ear and plays a vital role in forming connexons in the cells of the inner ear.",2737700,Cx32;137,Cx31;7338,N166;tmVar:p|Allele|N|166;VariantGroup:0;CorrespondingGene:2707;RS#:121908851,G199R;tmVar:p|SUB|G|199|R;HGVS:p.G199R;VariantGroup:17;CorrespondingGene:2705,0
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (@VARIANT$), @GENE$ (@VARIANT$) and @GENE$ (c.101T>G) genes.",7877624,SNAI2;31127,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In Family F, the @GENE$/235delC was inherited from the unaffected father and the A194T of @GENE$ was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the @VARIANT$/GJB3, while the mother is heterozygous for the GJB2/@VARIANT$ (Fig. 1k).",2737700,GJB2;2975,GJB3;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,1
"Using SIFT and PolyPhen, the c.1777C > G variant in @GENE$ was predicted to be damaging, but a different variant at the same amino acid, c.1777C > T (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants @VARIANT$ (p.Gly505Ser) in @GENE$ and @VARIANT$ (p.Asn118Ser) in MFSD8.",7463850,SLC9A6;55971,EHMT1;11698,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,c.353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"Co-segregation of TEK p.I148T and CYP1B1 @VARIANT$ was observed in two pedigrees and only a representative pedigree is shown. b Chromatograms of the four probands (lower panel) harboring the four different heterozygous @GENE$ mutations. The site of nucleotide change is indicated by an arrow, compared to the corresponding wild-type sequence (upper panel). c TEK protein sequence conservation across different species for the four mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A). The conserved residue for each mutation is highlighted in blue color. d Schematic representation of the TEK and CYP1B1 domains (Ig immunoglobulin, EGF epidermal growth factor, FN fibronectin, TM transmembrane, M membrane, H hinge region) indicating the location of the mutations identified in PCG (color figure online) TEK and CYP1B1 interact in cells. HEK293 were transiently transfected with indicated GFP-@GENE$ and HA-TEK plasmids.",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"This is in line with the data from previous studies; according to which, @GENE$ is a causative gene of ALS-FTD. The NEK1 R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    @GENE$ variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (@VARIANT$ and R572W). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form.",6707335,TBK1;22742,CCNF;1335,L106V;tmVar:p|SUB|L|106|V;HGVS:p.L106V;VariantGroup:7;CorrespondingGene:899;RS#:374191107,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (@VARIANT$, at 0.2%; p.Val134Gly, at 0.0008%; p.Arg262Gln at 0.2%; and @GENE$ @VARIANT$ at 0.0008%). Discussion The overall prevalence of @GENE$ mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies.",5527354,PROKR2;16368,GNRHR;350,p.Gln106Arg;tmVar:p|SUB|Q|106|R;HGVS:p.Q106R;VariantGroup:3;CorrespondingGene:2798;RS#:104893836;CA#:130197,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (@VARIANT$ or @VARIANT$); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, TG, DUOX2, DUOXA2, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases. Although dual oxidase 1 (@GENE$) and dual oxidase maturation factor 1 (@GENE$) have established roles in thyroid hormone production, relevant mutations associated with CH have not been found.",6098846,DUOX1;68136,DUOXA1;16043,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ c.109C>T. (b) Electropherograms of unaffected family member (II-2) and subject with BSP+ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of @VARIANT$ among vertebrates                @GENE$ missense variant A TOR2A nonsynonymous SNV (c.568C>T [NM_130459.3], @VARIANT$ [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,REEP4;11888,TOR2A;25260,Arg37;tmVar:p|Allele|R|37;VariantGroup:10;CorrespondingGene:80346;RS#:780399718,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Hence, priority should be given to identifying the @GENE$ @VARIANT$ mutation for preimplantation genetic diagnosis and/or chorionic villus sampling. Based on both clinical and laboratory quantification, it appears neither the TNFRSF13B/@GENE$ @VARIANT$ mutation nor the TCF3 T168fsX191 mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and @GENE$/TACI @VARIANT$ mutations. Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations are shown.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"Our study suggests that the KCNH2-@VARIANT$ variant has pathogenic properties consistent with LQTS. @GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, @VARIANT$, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS2;12122,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.763A > T;tmVar:c|SUB|A|763|T;HGVS:c.763A>T;VariantGroup:29;CorrespondingGene:55212,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"His cells produced higher levels of IgG and IgM than his mother (II.2, who bears both the TNFRSF13B/TACI @VARIANT$ and @GENE$ @VARIANT$ mutations).    The combination of TCF3 T168fsX191and @GENE$/TACI C104R mutations in the proband resulted in a greater net effect that the sum of each individual mutation would predict than the sum of deficits observed for each mutation alone (that is, Ig levelIII.2-(IgIII.2-IgIII.1)+(IgIII.2-IgII.3)).",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"The proband, who had LRP6 p.(@VARIANT$), p.(Ser127Thr), and @GENE$ p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth. The @GENE$ p.(Asn1075Ser) mutation substitutes highly-conserved asparagine with serine, which is predicted to destabilize the protein structure.",8621929,WNT10A;22525,LRP6;1747,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"  CSS161458 had a heterozygous splicing variant @VARIANT$ in RIPPLY1, as described above, and a heterozygous missense variant @VARIANT$(p.Arg155Leu) in MYOD1 was also identified. Although no direct interaction between RIPPLY1 and MYOD1 has been reported, they may together dysregulate the TBX6 pathway given the deleterious nature of both variants (Table 2).    DISCUSSION In this study, we performed exome sequencing on 584 patients with @GENE$ and without a molecular diagnosis. Variants in seven @GENE$-mediated genes involved in somitogenesis were selected for analysis.",7549550,CS;56073,TBX6;3389,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,c.464G>T;tmVar:c|SUB|G|464|T;HGVS:c.464G>T;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"                                 CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ p.307_308del and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 @VARIANT$ may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"(E) The @GENE$ mutation @VARIANT$ and @GENE$ mutation @VARIANT$ were found in patient S3, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.466C>T;tmVar:c|SUB|C|466|T;HGVS:c.466C>T;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the @GENE$ [GRCh37/hg19; chr10:@VARIANT$; NM_033056: @VARIANT$; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).,6053831,PCDH15;23401,USH1G;56113,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,c.3101G > A;tmVar:c|SUB|G|3101|A;HGVS:c.3101G>A;VariantGroup:2;CorrespondingGene:124590,0
"Importantly, he had no coexistent mutations in @GENE$, FGF8, FGFR1, PROK2, PROKR2, TAC3, TACR3, @GENE$, GNRHR, GNRH1, or KISS1R. The second patient (KS male C7) had a heterozygous c.757G>A (p.Ala253Thr) mutation (Figure 1; Table 1) affecting a completely conserved @VARIANT$ residue (Figures S1-4). Using multiple sequence alignment (ESPRESSO), a protein model for the N-terminus was constructed. Both SSPIDER and INTERPROSURF analysis (Figure S4) suggest functional importance for Ala253; and SIFT predicts a deleterious effect for p.Ala253Thr. Although p.Ala253Thr did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously.",3888818,CHD7;19067,KAL1;55445,Ala253;tmVar:p|Allele|A|253;VariantGroup:3;CorrespondingGene:26012;RS#:142726563,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"                  In this study, we identified nine reported gene variants, and we detected 13 novel variants: c.1525del A(@VARIANT$) and c.1524del A(p. Ser509fs) variants in the KAl1 gene; c.223 - 4C > A and c.306G > C(p. Arg102Ser) variant in the PROK2 gene: c.963dup A (p. Glu322fs), c.1695_1696insT(p. Lys566Ter), c.580G > T(p. Gly194Cys), c.1886 T > C(p. Val629Ala), @VARIANT$(p. Gly716Val), c.1081 + 1del, c.1974_ 1977del (p. Asn659fs), and c.75_ 78del (p. Thr26fs) variants in the @GENE$ gene; and c.875 T > C (p. Ile292Thr) variant in the @GENE$ gene.",8796337,FGFR1;69065,SEMA3A;31358,p. Ser509fs;tmVar:p|FS|S|509||;HGVS:p.S509fsX;VariantGroup:19;CorrespondingGene:3730,c.2147G > T;tmVar:c|SUB|G|2147|T;HGVS:c.2147G>T;VariantGroup:2;CorrespondingGene:2260,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Deleterious variants in HS1BP3 (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and @GENE$ were found in two or more independent pedigrees.",6081235,DNAH17;72102,MRPL15;32210,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,VAPB;36163,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 @VARIANT$, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (@GENE$ p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, @VARIANT$ was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,PTK7;43672,CELSR1;7665,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.R1044Q;tmVar:p|SUB|R|1044|Q;HGVS:p.R1044Q;VariantGroup:6;CorrespondingGene:23513;RS#:782787420;CA#:4918813,0
"   The substitutions of Leu117 to Phe (@VARIANT$), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether @GENE$ is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) @GENE$ (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,EphA2;20929,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to OPTN in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (CSF1R), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (FUS).       CNV analysis of the 21 neurodegenerative disease genes using Ingenuity Variant Analysis software further identified one patient with a partial deletion of OPTN (NM_001008211.1:c.1243-740_1612+1292delins25; @VARIANT$).",4470809,OPTN;11085,TBK1;22742,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,"p.Gly538Glufs27;tmVar:p|SUB|G|538,27|E;HGVS:p.G538,27E;VariantGroup:33;CorrespondingGene:10133",0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (p.Gly505Ser) in @GENE$ and c.353A > G (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language). Using Polyphen and MutationTaster, variants were predicted to possibly be damaging, but they were present in the ExAC database (EHMT1 @VARIANT$ at a rate of 4.95 x 10-5, MFSD8 @VARIANT$ at a rate of 8.24 x 10-6).",7463850,EHMT1;11698,MFSD8;115814,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,c. 353A > G;tmVar:c|SUB|A|353|G;HGVS:c.353A>G;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and @GENE$ (@VARIANT$).",3125325,MYO7A;219,USH2A;66151,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of @GENE$ and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,gap junction protein beta 3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in @GENE$ and @VARIANT$ in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous @VARIANT$ transition in exon 20, which results in an alanine to a serine (Ala771Ser) in MYO7A.",3949687,MYO7A;219,PCDH15;23401,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,2311G>T;tmVar:c|SUB|G|2311|T;HGVS:c.2311G>T;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; @VARIANT$, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, c.637G>A, @VARIANT$) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,g.112084C>G;tmVar:g|SUB|C|112084|G;HGVS:g.112084C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and p.R197C TTC26 proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type @GENE$ and wild-type FLNB, which did not exist between p.R2003H @GENE$ and @VARIANT$ OFD1 (figure 3D).",7279190,OFD1;2677,FLNB;37480,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, @VARIANT$ in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,MAP4K4;7442,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,0
"Six variants in @GENE$ occurred de-novo, three of which were not previously described: c.3236del p.(Asp1079Alafs*25), @VARIANT$ p.(Glu2954*), and @VARIANT$. One de-novo and novel variant was also detected in @GENE$: c.992G>A p.(Cys331Tyr).",7224062,PKD1;250,PKD2;20104,c.8860G>T;tmVar:c|SUB|G|8860|T;HGVS:c.8860G>T;VariantGroup:46;CorrespondingGene:5310,c.9201+1G>A;tmVar:c|SUB|G|9201+1|A;HGVS:c.9201+1G>A;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,0
"    A new pathogenic variant in @GENE$ affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; @VARIANT$) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in @GENE$ that leads to a @VARIANT$, c.763A > T, was identified in patient #3.",6567512,BBS2;12122,BBS7;12395,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"There is a splicing site mutation @VARIANT$ in @GENE$, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A3;68033,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"For example, two variants in proband P15, @VARIANT$ in PROKR2 and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while @GENE$ p. Gln1626His variant was inherited from unaffected mother.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DMXL2;41022,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,0
"Although @VARIANT$ did not alter splicing or quantitative mRNA expression (not shown), lymphoblast protein expression was consistently reduced by 50% in vitro. This p.Ala253Thr mutation was identified in a male with sporadic KS, unilateral renal agenesis, and partial pubertal development. He also had a KAL1 deletion (c.488_490delGTT;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, @GENE$, @GENE$, PROK2, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,FGF8;7715,FGFR1;69065,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Exome sequencing performed with DNA from Patient 3 identified 13 homozygous variants that were rare and predicted to be deleterious (Table S1 in the Supplementary Appendix), 2 of which were also homozygous in the two other affected siblings: RNF216 (NM_207111.3) c.2251C T, @VARIANT$ and @GENE$ (NM_001102653.1) c.998G T, @VARIANT$; these variants were not identified or were heterozygous in the unaffected family members (Fig. 1). @GENE$ encodes an E3 ubiquitin-protein ligase.",3738065,OTUD4;35370,RNF216;19442,p.R751C;tmVar:p|SUB|R|751|C;HGVS:p.R751C;VariantGroup:1;CorrespondingGene:54476;RS#:387907368;CA#:143853,p.G333V;tmVar:p|SUB|G|333|V;HGVS:p.G333V;VariantGroup:4;CorrespondingGene:54726;RS#:148857745;CA#:143858,0
Representative western blot and bar graph showing expression levels of SEC23A (A) and @GENE$ (B) proteins in wild-type (Wt); @GENE$ M400I/+ heterozygous; SEC23AM400I/+ MAN1B1R334C/+ double heterozygous; and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double homozygous mutant fibroblasts.,4853519,MAN1B1;5230,SEC23A;4642,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"In summary, we investigated an extremely rare large ERS family with a high incidence of nocturnal SCD, in which we found a pathogenic mutation in @GENE$ (@VARIANT$) with loss-of-function. The penetrance was also incomplete, which was modified by a gain-of-functional @GENE$-@VARIANT$ variant and sex.",5426766,CACNA1C;55484,SCN5A;22738,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,1
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0
"Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, GRIN2A @VARIANT$ (p.Leu10Met) and @GENE$ @VARIANT$ (p.Arg248Cys). The variant in @GENE$ was novel and was predicted to be damaging using both SIFT and PolyPhen.",7463850,PLXNB2;66630,GRIN2A;645,c.28C > A;tmVar:c|SUB|C|28|A;HGVS:c.28C>A;VariantGroup:0;CorrespondingGene:2903,c.742C > T;tmVar:c|SUB|C|742|T;HGVS:c.742C>T;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in @GENE$ (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Mutagenesis Sequence variants @GENE$-@VARIANT$ (p.C108Y) and @GENE$-@VARIANT$ (p.R583H) were introduced into KCNH2 and KCNQ1 cDNAs, respectively, as described previously.",5578023,KCNH2;201,KCNQ1;85014,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"The @GENE$ pathway is very important in regulating the intestinal inflammation, and mutations in the receptor cancel the IL-10 immunomodulatory signal, which is strongly associated with an intestinal hyper-inflammation. Although there are no data about the association between these variants (@VARIANT$ and R351G) and the early onset of the disease, several studies have shown a loss of function due to these variants. @GENE$, localized at chromosome 16q21, codify for a protein that belongs to the family of intracellular NLR (NOD-like receptors), able to recognize microbial components and to stimulate an inflammatory response through the activation of NF-kappaB. Moreover, three NOD2 mutations (rs2066844, rs2066845 and @VARIANT$) represent the main genetic factor causing susceptibility to CD.",3975370,IL-10;478,NOD2;11156,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,rs5743293;tmVar:rs5743293;VariantGroup:18;RS#:5743293,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b). These @GENE$ mutations were predicted to be pathological by several in silico prediction software programs (Supplementary Table 1). The patient carrying @VARIANT$ of @GENE$ was previously reported.",7067772,EPHA2;20929,SLC26A4;20132,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of @GENE$ (@VARIANT$)::CYP1B1 (p.A115P), TEK (p.Q214P)::@GENE$ (@VARIANT$), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1). A compound heterozygous TEK mutation (p.E103D and p.E300G) was also observed in 1 family (PCG38). However, the remaining 20 PCG cases harboring a single heterozygous TEK mutation did not carry any additional mutation in the other 35 adult and childhood glaucoma-associated genes (Supplementary Fig. 1; Supplementary Table 1). The co-occurrence of heterozygous TEK and @GENE$ mutations as seen in our PCG cases were not observed in additional sets of POAG, ARS, Aniridia, and Peter's Anomaly patients.",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of @GENE$ and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"   The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (@VARIANT$), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of @GENE$ caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with @GENE$ was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Sequence alterations were detected in the COL6A3 (@VARIANT$), @GENE$ (rs143445685), @GENE$ (@VARIANT$), and DES (rs144901249) genes.",6180278,RYR1;68069,CAPN3;52,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"So, it is impossible to detect a mutation in a region which is not covered using this system (Case #9: @VARIANT$). Secondarily, the MPS system used in this study, is not effective for detecting homo-polymer regions, for example poly C stretch (Case #8: @VARIANT$). In addition, concerning pathogenecity of mutations identified, functional analysis will be necessary to draw the final conclusion in the future. In UK and US Caucasian USH1 patients, USH1B (@GENE$) has been reported as the most common USH1 genetic subtype, while USH1F (@GENE$) has been reported as the most common USH1 genetic subtype in North American Ashkenazi Jews.",3949687,MYO7A;219,PCDH15;23401,c.5821-2A>G;tmVar:c|SUB|A|5821-2|G;HGVS:c.5821-2A>G;VariantGroup:42;CorrespondingGene:64072,p.Lys542GlnfsX5;tmVar:p|FS|K|542|Q|5;HGVS:p.K542QfsX5;VariantGroup:6;CorrespondingGene:4647;RS#:782077721;CA#:6197531,0
"Sanger sequencing was further performed for validation of the identified variants and analysis of their segregation within each family, using corresponding primer sets for @GENE$ and @GENE$. For numbering gDNA and cDNA mutation positions, the subject's sequence variants were compared to human reference sequences NG_016168.2 and NM_002336.3 for LRP6 and NG_012179.1 and NM_025216.3 for WNT10A.       2.3. Prediction of Structural Alterations Caused by LRP6 Mutations To investigate the potential impact of the identified LRP6 missense mutations on protein structure we conducted computational predictions using PremPS, recently developed software that has been shown to outperform currently available methods. For prediction of p.Ser127Thr and @VARIANT$ the PDB (Protein Data Bank) structure of 3S94 was used, which constituted a crystal structure of the human LRP6 extracellular domain (E1E2). On the other hand, 4A0P, the crystal structure of LRP6-E3E4, was employed for prediction of @VARIANT$, p.Ser817Cys, and p.Asn1075Ser. ""A chain"" was selected in all predictions, and mutation specified manually.",8621929,LRP6;1747,WNT10A;22525,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.Ala754Pro;tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of @GENE$ and @GENE$ by co-transfection and pull-down assays in HEK293 cells.",5953556,TEK;397,CYP1B1;68035,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"To sum up, SH166-367, SH170-377, and SB175-334 which would have been considered @GENE$ without TES were found to be DFNB7/11, DFNB3, and DFNB16, respectively.  Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (@GENE$) (NM_001145853) according to TES.",4998745,DFNB1;2975,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Coincidentally, PFBC patients with variants in both a PFBC pathogenic gene (SLC20A2 or @GENE$) and another PFBC-unrelated gene (THAP1, @GENE$, CASR, SCN2A or MEA6) were described as presenting more complex phenotypes, supporting the notion that a variant of a second gene may promote a heterogeneous phenotype in PFBC patients (Baker et al., 2014; Borges-Medeiros & de Oliveira, 2020; DeMeo et al., 2018; Fjaer et al., 2015; Fujioka et al., 2015; Knowles et al., 2018). The SLC20A2 c.1787A>G (@VARIANT$) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the PDGFRB c.317G>C (@VARIANT$) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,PDGFRB;1960,CHRNB2;595,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"@GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-@VARIANT$ heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP.",6081235,TOR2A;25260,GNA14;68386,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 @VARIANT$), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD;8321;8323,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0
"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, p.Arg896Trp) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,1
"The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(@VARIANT$). Both fetuses inherited the maternal @GENE$ missense variant, in addition to the paternal p.(Ser872Gly) variant in PKD1, while only one fetus inherited the p.(Arg872Gly) PKD2 variant. The analysis of @GENE$ performed on the first fetus showed no mutations.",7224062,PKD2;20104,PKHD1;16336,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"However, the proband's younger brother and father were heterozygous carriers of the @VARIANT$ mutation in the @GENE$ gene while they also carried the p.R1141X mutation in the ABCC6 gene; they did not display any signs of cutaneous findings or hematologic disorder.       Assay of gamma-glutamyl carboxylase activity Previous studies have clearly demonstrated that the @VARIANT$ mutation in the @GENE$ gene in heterozygous carriers does not cause PXE.",2900916,GGCX;639,ABCC6;55559,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, @GENE$ @VARIANT$, PTK7 @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, @VARIANT$ and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.3719G>A;tmVar:c|SUB|G|3719|A;HGVS:c.3719G>A;VariantGroup:87;CorrespondingGene:4647;RS#:542400234;CA#:5545997,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"  To gain further insight into the role of EphA2 on pendrin regulation, @GENE$ A372V, L445W, Q446R or G672E was co-overexpressed with EphA2. The cells were transfected with cDNAs of encoding myc-pendrin diease forms with that of EphA2, and the non-permeable cells were stained with an anti-myc antibody. While signal corresponding to myc-pendrin was observed in ~65% of cells, ratio of V5-pendrin A372V, L445W, Q446R, or G672E positive cells was significantly decreased (Supplementary Fig. 5a, b). Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin A372V, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (@VARIANT$), identified in Pendred syndrome patients, do not affect their membrane localization.",7067772,pendrin;20132,EphA2;20929,Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F335L;tmVar:p|SUB|F|335|L;HGVS:p.F335L;VariantGroup:20;CorrespondingGene:13836,0
"Sequence alterations were detected in the COL6A3 (@VARIANT$), RYR1 (@VARIANT$), @GENE$ (rs138172448), and @GENE$ (rs144901249) genes.",6180278,CAPN3;52,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,0
"This is in line with the data from previous studies; according to which, @GENE$ is a causative gene of ALS-FTD. The NEK1 R261H variant was also present in this patient. A combined effect of the two major ALS gene variants may contribute to the early onset and fast progression of the disease in patient #90.    CCNF variants are a rare cause of ALS-FTD; in diverse geographic familial cohorts, variants in CCNF were present at frequencies ranging from 0.6 to 3.3%. In this Hungarian cohort, we identified two patients (1.9%) with CCNF variants (@VARIANT$ and R572W). The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the @GENE$ gene, both in heterozygous form.",6707335,TBK1;22742,ALS2;23264,L106V;tmVar:p|SUB|L|106|V;HGVS:p.L106V;VariantGroup:7;CorrespondingGene:899;RS#:374191107,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"One patient carried two de novo variants in the @GENE$ gene, the aforementioned small deletion, and a missense mutation in a moderately conserved amino acid (p.I61M). One patient was found to carry a de novo 9bp deletion in @GENE$, which was out of frame, therefore deleting four amino acids and inserting an arginine in a highly conserved domain of the protein. Of note, this particular patient did not have a history of tuberous sclerosis, or a positive family history of tuberous sclerosis. The Simons Simplex Collection database does not contain information about brain imaging studies; however, it is documented that this patient has a history of seizures. Another patient carried a de novo missense mutation in PTEN, altering a moderately conserved threonine to an alanine (@VARIANT$). The patient has no known history or documented features of PTEN harmatoma tumor syndrome and his head circumference was at the 25th percentile. Lastly, two patients carried de novo mutations in the FOXP2 gene. One had a missense variant of an amino acid that is conserved throughout species (@VARIANT$) and another patient had a 3 bp insertion, adding a glutamine in yet another highly conserved domain of the protein (Fig. 1).",3153303,HOXA1;4032,TSC2;462,p.T78A;tmVar:p|SUB|T|78|A;HGVS:p.T78A;VariantGroup:2;CorrespondingGene:7337,p.H603P;tmVar:p|SUB|H|603|P;HGVS:p.H603P;VariantGroup:3;CorrespondingGene:93986,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant @VARIANT$ and a novel FAT4 missense variant @VARIANT$).",5887939,CELSR2;1078,FAT4;14377,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"These phenomenon indicate that the mutated SCAP-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated @GENE$ coding protein. @GENE$-@VARIANT$ (p.Ala338Val) variant impaired the catabolism of ADMA in EA.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (p.N382S/@VARIANT$) and MYO6 (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"Given the reported normal function of pendrin @VARIANT$ and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 p.T410M mutations.",7067772,ephrin-B2;3019,pendrin;20132,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (rs144651558), RYR1 (@VARIANT$), CAPN3 (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,COL6A3;37917,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, @VARIANT$) were detected.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"We identified two subjects with sporadic ALS who harboured a different variant at the same codon: @VARIANT$, and another alteration two amino acids away: @VARIANT$. Both of these DAO mutants are predicted to be damaging by PhyloP, SIFT, PolyPhen and LRT, and were not found in our control samples. Our large-scale sequencing study in ALS has identified a number of rare variations, many novel, and shown that the UTR of @GENE$ and @GENE$ are potentially important in the pathogenesis of ALS.",5445258,TARDBP;7221,FUS;2521,R199Q;tmVar:p|SUB|R|199|Q;HGVS:p.R199Q;VariantGroup:16;CorrespondingGene:1610;RS#:139166976,Q201R;tmVar:p|SUB|Q|201|R;HGVS:p.Q201R;VariantGroup:57;CorrespondingGene:6647,0
"Most intriguingly, the more severely affected of the two patients, Patient 3, was found to harbor a known heterozygous variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), a testes determining gene associated with heart anomalies, and this variant has been previously reported in an individual with diaphragmatic hernia (Bleyl et al., 2007). We postulate that the cumulative effect of these changes in two different genes may be contributing to the patient's more severe phenotype.           In a second example, we identified a monoallelic change in @GENE$ (@VARIANT$, p.Arg227Gln, rs9332964:G>A), in conjunction with the single amino acid deletion at position 372 of SF1.",5765430,ZFPM2;8008,SRD5A2;37292,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in @GENE$. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and SETX p.T14I).",4293318,VAPB;36163,ATXN2;2234,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, @VARIANT$, p.Tyr27His), @GENE$ (NM_018328.4, @VARIANT$, p.Leu667Trp), and NRXN1 (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,MBD5;81861,c.79T>C;tmVar:c|SUB|T|79|C;HGVS:c.79T>C;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"4.4. Cell Culture and Heterologous Expression Chinese hamster ovaries (CHO-K1, American Type Culture Collection) were grown in F-12 HAM nutrient mixture medium (11765-054, ThermoFischer Scientific Inc., Waltham, MA, USA) supplemented with 10% fetal bovine serum (ThermoFisher Scientific Inc., Waltham, MA, USA), 2 mM l-glutamine, 50 U/mL penicillin, and 50 mug/mL streptomycin (Sigma, St. Louis, MO, USA) in a humidified 5% CO2 atmosphere at 37  C. Cells were transfected using Fugene 6 (Roche, Mannheim, Germany) in 21 cm2 dishes with 1 mug (KCNQ1-WT or @GENE$-@VARIANT$) or 1.5 mug (@GENE$-WT or KCNH2-@VARIANT$) plasmid/dish in transient transfection experiments.",5578023,KCNQ1;85014,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"4.4. Cell Culture and Heterologous Expression Chinese hamster ovaries (CHO-K1, American Type Culture Collection) were grown in F-12 HAM nutrient mixture medium (11765-054, ThermoFischer Scientific Inc., Waltham, MA, USA) supplemented with 10% fetal bovine serum (ThermoFisher Scientific Inc., Waltham, MA, USA), 2 mM l-glutamine, 50 U/mL penicillin, and 50 mug/mL streptomycin (Sigma, St. Louis, MO, USA) in a humidified 5% CO2 atmosphere at 37  C. Cells were transfected using Fugene 6 (Roche, Mannheim, Germany) in 21 cm2 dishes with 1 mug (@GENE$-WT or KCNQ1-@VARIANT$) or 1.5 mug (@GENE$-WT or KCNH2-@VARIANT$) plasmid/dish in transient transfection experiments.",5578023,KCNQ1;85014,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,0
"Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the @GENE$ (NM_000179.2: @VARIANT$, p.Thr1100Met) and @GENE$ (NM_001128425.1: @VARIANT$, p.Tyr179Cys) genes, while the other 20 genes could not be clearly linked to cancer predisposition.",7689793,MSH6;149,MUTYH;8156,c.3299C > T;tmVar:c|SUB|C|3299|T;HGVS:c.3299C>T;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.536A > G;tmVar:c|SUB|A|536|G;HGVS:c.536A>G;VariantGroup:15;CorrespondingGene:4595;RS#:145090475;CA#:7607273,1
"Furthermore, these missense mutations were either unreported in the ExAC population database (p.Arg139Cys, and p.Tyr283His) or reported at rare frequencies (p.Gln106Arg, at 0.2%; @VARIANT$, at 0.0008%; p.Arg262Gln at 0.2%; and @GENE$ @VARIANT$ at 0.0008%). Discussion The overall prevalence of @GENE$ mutations in this cohort was 12.5% (five out of 40 patients with nCHH), which is consistent with results presented in other studies.",5527354,PROKR2;16368,GNRHR;350,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"Moreover, the presence of other variants (@GENE$-@VARIANT$, KCNH2-p.K897T, and KCNE1-p.G38S) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype. On the contrary, in the mother, some other factors, including unknown genetic modifiers, could counteract the functional impairment of mutant channels, thereby protecting the asymptomatic @GENE$-@VARIANT$ mutation-positive subject from arrhythmia susceptibility.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,1
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and @VARIANT$; PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6).",6610752,KCNH2;201,KCNE2;71688,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Mice lacking @GENE$ develop cardiomyopathy and have an increased frequency of sudden death upon stress; electron microscopy of these mice revealed malformed blood vessels and micro-circulation abnormalities. Moreover, patients carrying a LAMA4 @VARIANT$ mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (L1038P) and @GENE$ (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and TNNT2 (@VARIANT$), both sarcomeric genes.",6359299,LAMA4;37604,MYBPC3;215,Pro943Leu;tmVar:p|SUB|P|943|L;HGVS:p.P943L;VariantGroup:5;CorrespondingGene:3910;RS#:387907365;CA#:143749,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0
(B) The predicted 2D structure of human @GENE$ protein. The @VARIANT$ and G213 residues are in yellow. The 3D structure of @GENE$ is shown in Figure 4. The @VARIANT$ residue is located at the interface of two trimers.,3842385,WNT10A;22525,EDA;1896,R171;tmVar:p|Allele|R|171;VariantGroup:3;CorrespondingGene:80326;RS#:116998555,G257;tmVar:c|Allele|G|257;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (@VARIANT$) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"20  The identified CUX1 (NM_001202543: @VARIANT$, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The @GENE$ (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, @GENE$ variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis.",7689793,RYR3;68151,TRIP6;37757,c.1438A > G;tmVar:c|SUB|A|1438|G;HGVS:c.1438A>G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"The pathogenicity of the @VARIANT$ mutation in @GENE$  is, however, questionable since we found it in five alleles from the control population. The @VARIANT$ mutation in @GENE$, leading to an in frame-deletion of a threonine residue (p.T1868del) within the intracellular domain of the protocadherin-15 CD1 isoform, also warrants a special mention.",3125325,CDH23;11142,PCDH15;23401,p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387,c.5601delAAC;tmVar:p|DEL|C.5601|N;HGVS:p.C.5601delN;VariantGroup:316;CorrespondingGene:65217,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,UBQLN2;81830,FUS;2521,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"We observed that recombinant @GENE$ and @GENE$ proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (@VARIANT$), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (@VARIANT$)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, c.921_923del), and DMD p.E1028V (NM_004011, @VARIANT$) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, @GENE$ gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of KCNH2 and SCN5A genes are closely related to LQTS. The mutations of KCNH2 p.307_308del and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.       Additionally, the heterozygous @GENE$ @VARIANT$ was carried by I: 1 and II: 2, but not carried by I: 2 (Figure 1a).",8739608,KCNH2;201,SCN5A;22738,c.A3083T;tmVar:c|SUB|A|3083|T;HGVS:c.3083A>T;VariantGroup:5;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C TTC26 proteins pulled down the Flag-tagged mutant p.A2282T and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the @VARIANT$ residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the @GENE$ mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with @GENE$. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between p.R2003H FLNB and p.Y437F OFD1 (figure 3D).",7279190,FLNB;37480,OFD1;2677,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,R2003;tmVar:R2003;VariantGroup:29;CorrespondingGene:2317,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant @VARIANT$ and a novel @GENE$ missense variant @VARIANT$).",5887939,FZD1;20750,FAT4;14377,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,1
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 @VARIANT$, @GENE$ p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,SCRIB;44228,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). The c.1787A>G (@VARIANT$) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (@GENE$ @VARIANT$ and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A).",5887939,CELSR1;7665,DVL3;20928,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,1
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, @GENE$ @VARIANT$, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (@GENE$ p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and @VARIANT$ localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, p.G1108E located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,PTK7;43672,CELSR1;7665,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,GJB6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"NGS reads indicated the identification of homozygous missense pathogenic variants @VARIANT$ (p.R758C) and c.850C>T (@VARIANT$) in ANO5 and SGCA genes, respectively. (B) Rapid disease progression was observed in a 16-year-old male (arrow) with two pathogenic variants in ANO5 gene and one pathogenic variant in @GENE$ gene indicating multiple gene contributions for an unusual presentation. His mother, a 40-year-old female with one pathogenic variant each in ANO5 and COL6A2 shows unspecified myopathy with elevated creatine phosphokinase (CPK).         Deep intronic variant in @GENE$ gene Recently, we characterized a deep intronic mRNA splice-altering pathogenic variant c.4886 + 1249G>T in DYSF gene that inserts a novel 177 bp pseudoexon at the exon 44-45 junction.",6292381,COL6A2;1392,DYSF;20748,c.2272C>T;tmVar:c|SUB|C|2272|T;HGVS:c.2272C>T;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,R284C;tmVar:p|SUB|R|284|C;HGVS:p.R284C;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The @VARIANT$ and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (CSF1R), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (FUS).       CNV analysis of the 21 neurodegenerative disease genes using Ingenuity Variant Analysis software further identified one patient with a partial deletion of @GENE$ (NM_001008211.1:c.1243-740_1612+1292delins25; p.Gly538Glufs27).",4470809,TBK1;22742,OPTN;11085,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"Interestingly, four of these TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::@GENE$ (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of TEK to respond to ligand stimulation, indicating perturbed @GENE$ signaling.",5953556,CYP1B1;68035,TEK;397,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"      Mutation detection in the family (a) Identification of the recurrent nonsense mutation p.R1141X in the @GENE$ gene. Note the heterozygous @VARIANT$ transition substitution at nucleotide position 3421 (arrow). (b, d) Identification of missense mutations @VARIANT$ and p.S300F in the @GENE$ gene.",2900916,ABCC6;55559,GGCX;639,C T;tmVar:c|Allele|CT|;VariantGroup:26;CorrespondingGene:368,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"We identified a novel compound heterozygous variant in BBS1 @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS2;12122,BBS6;10318,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The @VARIANT$ (p.R77C) variant in S100A3 and @VARIANT$ (p.I80Gfs*13) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2.             Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, S100A13 and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.",6637284,S100A13;7523,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"In this family, the @GENE$/TACI C104R mutation appears to demonstrate a gene dosage effect on serum IgG levels. The brother who is homozygous (II.4) for the TNFRSF13B/TACI @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the @GENE$ T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"This de novo variant may modify the effect of the truncating variant in ENG by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in @GENE$ inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2).",6161649,BMP;55955,ENG;92,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, @GENE$ @VARIANT$ and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2). Among these variants, p.R769W and p.R1057C localized to the carbonic anhydrases subunits, named the CA domain of CELSR1, p.R1044Q was within the third PDZ domain of SCRIB, @VARIANT$ located very close to the fourth PDZ domain (1109-1192) of SCRIB, and p.P642R was within the fifth IGc2 domain of PTK7 (Supplemental Material, Fig. S3).",5966321,SCRIB;44228,CELSR1;7665,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Out of the remaining 10 variants, 4 were detected in TANK-binding kinase 1 (TBK1), two in leucine rich repeat kinase 2 (LRRK2), one in @GENE$ (OPTN), one in fused in sarcoma (FUS), one in profilin 1 (PFN1) and one in the colony stimulating factor 1 receptor (@GENE$). Importantly, when we sorted these 10 remaining variants by pathogenicity score based on CADD_Phred score, all 4 TBK1 variants and the OPTN variant had scores higher than 20, meaning that those substitutions are predicted to be among the 1% most deleterious substitutions in the human genome (Table 1; Figure 1a). Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; @VARIANT$), and TBK1 (NM_013254.3:c.349C>T; p.Arg117*) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes.",4470809,optineurin;11085,CSF1R;3817,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,0
"M1, @GENE$: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, CYP1B1: @VARIANT$. M4, PITX2: p.(P179T). M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(E173*);tmVar:p|SUB|E|173|*;HGVS:p.E173*;VariantGroup:11;CorrespondingGene:1545,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"The brother who is homozygous (II.4) for the @GENE$/TACI @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the TCF3 T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree.",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
   Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the @GENE$ gene and in exon 4 (c.872 C > G; @VARIANT$) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the GCK variant was present in the father and the @GENE$ variant was present in the mother (Figure 1B).,8306687,GCK;55440,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"Thus, the presence of combined mutations in @GENE$ and @GENE$ results in reduced pro-COL1A1 in the ER. Colocalization of pro-COL1A1 with endoplasmic reticulum (ER) was reduced in patient fibroblasts. Protein disulfide isomerase (PDI) (green; A,D,G,J), a marker of ER lumen, and intracellular pro-COL1A1 (red; B,E,H,K) were visualized using immunofluorescence microscopy. Merged images showing pro-COL1A1 colocalization with PDI in wild-type (Wt) (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ MAN1B1R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double homozygous (L) fibroblasts.",4853519,SEC23A;4642,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"A single control also had two mutations, @VARIANT$ in @GENE$ and @VARIANT$ in TARDBP. ALS2 pathogenicity has only been observed in homozygotes, and this individual was heterozygous. Furthermore, the TARDBP variant has been previously identified in controls and has unclear status, although it is associated with abnormal localization and aggregation of TARDBP. What constitutes a pathogenic combination of mutations is debatable as some variants are of uncertain significance, and the combination of a pathogenic variant with one of uncertain significance has been considered oligogenic inheritance by some. Similarly, variation in ANG or NEFH is generally considered a weak contributor to ALS risk, and missense variants in @GENE$ are often benign unless resulting in loss of function.",5445258,ALS2;23264,SPG11;41614,P372R;tmVar:p|SUB|P|372|R;HGVS:p.P372R;VariantGroup:36;CorrespondingGene:57679;RS#:190369242;CA#:2058513,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of @GENE$) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel @GENE$ missense variant @VARIANT$).",5887939,CELSR2;1078,FAT4;14377,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"2.3. Functional Consequences of the KCNQ1-@VARIANT$ and KCNH2-p.C108Y Variants To investigate the functional consequences of @GENE$-p.R583H and @GENE$-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,UBQLN2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and @GENE$ p.R408C with @GENE$ p.I2547T and SETX @VARIANT$).,4293318,TAF15;131088,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"We identified four genetic variants (@GENE$-@VARIANT$, @GENE$-p.C108Y, KCNH2-p.K897T, and KCNE1-@VARIANT$) in an LQTS family.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Our results indicate that the novel @GENE$-C108Y variant can be a pathogenic LQTS mutation, whereas @GENE$-p.R583H, KCNH2-@VARIANT$, and KCNE1-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNQ1;85014,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Among the variants identified in @GENE$, four are known variants, and one, is a novel missense variant at the exon 9 (c.2857A > G @VARIANT$) present in heterozygosis (Figure 1B). Within the three variants in the coding sequence of @GENE$, two missense variants, both present in heterozygosis, rs3135932 (c.475A > G p. S159G) and rs2229113 (c.1051 G > A @VARIANT$), have already been described in the literature.",3975370,NOD2;11156,IL10RA;1196,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,p.G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue TCF3 @VARIANT$ mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the T168fsX191 mutation of @GENE$ and C104R (@VARIANT$) mutation of TACI gene in the proband II.2. The proband's son (III.1) has inherited the TCF3 T168fsX191 mutation, but not the @GENE$/TACI C104R mutation.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,c.310T>C;tmVar:c|SUB|T|310|C;HGVS:c.310T>C;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and @GENE$ (@VARIANT$).",3125325,MYO7A;219,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,1
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,USH2A;66151,CDH23;11142,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"On the other hand, no disease-causing digenic combinations included the @GENE$ gene variant @VARIANT$. The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; p.(Glu587Lys)] was only present in HH12 and absent in his asymptomatic mother (Figure 1).",8446458,PROKR2;16368,SEMA7A;2678,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (@VARIANT$ causing a frameshift p.I80Gfs*13) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"For example, two variants in proband P15, @VARIANT$ in PROKR2 and p. Tyr503His in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother.",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"Pedigree and sequence chromatograms of the patient with the @VARIANT$ in MYO7A and @VARIANT$ in @GENE$ mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (Ala771Ser) in @GENE$. Another variation, 158-1G>A in intron 3 of PCDH15, was derived from the proband and his father.",3949687,PCDH15;23401,MYO7A;219,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP @VARIANT$ was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,VAPB;36163,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 p.A961T (NM_000426, c.G2881A), KCNH2 p.307_308del (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. SCN5A gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database). Mutations of @GENE$ and @GENE$ genes are closely related to LQTS. The mutations of KCNH2 @VARIANT$ and SCN5A p.R1865H were found in the proband by WES and validated as positive by Sanger sequencing.",8739608,KCNH2;201,SCN5A;22738,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ I148T (~70%). No significant change was observed with HA-TEK @VARIANT$ with GFP-@GENE$ @VARIANT$ as compared to WT proteins (Fig. 2).,5953556,TEK;397,CYP1B1;68035,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Four genes (including AGXT2, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and @GENE$-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"Therefore, @GENE$ genotyping has not yet entered into clinical practice. On the basis of the data collected in this study, we may speculate that the presence of KCNH2-@VARIANT$, together with three @GENE$-@VARIANT$ alleles, could lead to an increased risk of developing cardiac arrhythmias due to the prolongation of the QT interval.",5578023,NOS1AP;136252,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"He also had a KAL1 deletion (@VARIANT$;@VARIANT$) (Table 1; Figure 1B) we characterized previously. This in-frame deletion removes a fully conserved cysteine residue in the anosmin-1 protein encoded by KAL1 (Figure S1C,D). The KS proband with NELF/KAL1 mutations had no mutations in CHD7, @GENE$, @GENE$, PROK2, PROKR2, TAC3, TACR3, GNRHR, GNRH1, or KISS1R.",3888818,FGF8;7715,FGFR1;69065,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,KCNE2;71688,KCNH2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Of the 3 novel variants in DUOX2, @VARIANT$ was a frameshift mutation and had a potential deleterious effect on protein function and p.D137E and @VARIANT$ were missense mutations located in the peroxidase-like domain (Fig. S3A).  A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, DUOX2, @GENE$ and TPO).",7248516,SLC26A4;20132,DUOXA2;57037,p.T803fs;tmVar:p|FS|T|803||;HGVS:p.T803fsX;VariantGroup:61;CorrespondingGene:50506,p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by @GENE$. 20  The identified CUX1 (NM_001202543: c.1438A > G, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and @GENE$. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: @VARIANT$, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,OGG1;1909,CAPN9;38208,c.1034A > T;tmVar:c|SUB|A|1034|T;HGVS:c.1034A>T;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for @GENE$ (Cx26) and @GENE$ (Cx31) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,connexin 26;2975,connexin 31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The @VARIANT$ and R393Q variants are known variants reported by other study groups.",6707335,GRN;1577,SQSTM1;31202,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"In the individual carrying the P505L NEFH variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C p. Arg1299Cys). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the CCDC88C @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (@GENE$) p. Thr584Serfs*5, and the rest were missense variants.",8152424,FGFR1;69065,IGSF10;18712,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in @GENE$ (c.1175C>T, @VARIANT$) and a heterozygous variant in @GENE$ (@VARIANT$, p.Asn357Ser).",5868303,SQSTM1;31202,TIA1;20692,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Colocalization of pro-COL1A1 and @GENE$ was significantly increased in cells with heterozygous (P < 0.05 ANOVA) and homozygous (P < 0.01, ANOVA) mutations in both genes (Fig. 7, cf. I,L and C,F) when compared with wild type and cells with heterozygous mutation in SEC23A (Table 5; Supplemental Fig. S6). Thus, combined mutations in SEC23A and MAN1B1 result in retention of pro-COL1A1 in the Golgi. Colocalization of pro-@GENE$ with trans-Golgi was increased in patient fibroblasts. TGN38 (green; A,D,G,J), a marker of trans-Golgi, and intracellular pro-COL1A1 (red; B,E,H, K) were visualized using immunofluorescence microscopy. Merged images showing pro-COL1A1 colocalization with TGN38 in wild-type (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ MAN1B1R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double-homozygous (L) fibroblasts.",4853519,TGN38;136490,COL1A1;73874,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant @VARIANT$ and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between p.R2003H FLNB and @VARIANT$ OFD1 (figure 3D).",7279190,FLNB;37480,TTC26;11786,p.A2282T;tmVar:p|SUB|A|2282|T;HGVS:p.A2282T;VariantGroup:6;CorrespondingGene:2317;RS#:1339176246,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"Her son, III.1, carrying the @GENE$ @VARIANT$ mutation only, also generated a similar proportion of IgG+ switched cells. However, individuals carrying the @GENE$/TACI @VARIANT$ mutation alone (II.3 and II.4) generated fewer IgG+ switched cells from naive cultures, even in the absence of TACI ligand engagement.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 @GENE$, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by @GENE$. 20  The identified CUX1 (NM_001202543: c.1438A > G, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: @VARIANT$, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS.",7689793,CUX1;22551,OGG1;1909,c.822G > C;tmVar:c|SUB|G|822|C;HGVS:c.822G>C;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"For co-transfection experiments, 2 mug (1 mug KCNQ1-WT + 1 mug @GENE$-WT or 1 mug KCNQ1-@VARIANT$ + 1 mug KCNE1-WT) or 3 mug (1.5 mug @GENE$-WT + 1.5 mug KCNH2-@VARIANT$ or 1.5 mug KCNH2-WT + 1.5 mug empty vector) plasmid per dish were used.",5578023,KCNE1;3753,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,0
"The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein. However, the two rare @GENE$ variants (Y25C and P106L) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein. Although the majority of FUS mutations linked to ALS are located in the extreme C-terminus of the protein, several studies show that N-terminal variants may also be damaging.       In the TBK1 gene, a known missense variant (I397T) and a novel non-frameshift deletion (@VARIANT$) were identified in our patient cohort.",6707335,ubiquilin-2;81830,FUS;2521,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,K631del;tmVar:p|DEL|631|K;HGVS:p.631delK;VariantGroup:53;CorrespondingGene:29110,0
"  Digenic inheritances of GJB2/@GENE$ and GJB2/GJB3 (group II). (A) In addition to c.235delC in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic p.A194T variant of GJB3. @GENE$ = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D).",4998745,MITF;4892,DFNB1;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The @VARIANT$ (@VARIANT$) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and WNT10A mutations at the same locus as that of N2 (Fig. 2B).",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"20  The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include @GENE$, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS.",7689793,RYR3;68151,TRIP6;37757,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (@VARIANT$) and @GENE$: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,p.G355R;tmVar:p|SUB|G|355|R;HGVS:p.G355R;VariantGroup:4;CorrespondingGene:1969;RS#:370923409;CA#:625329,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (c.229C>T; p.R77C) and d) the c.238-241delATTG (p.I80Gfs*13) in @GENE$. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.    Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, @VARIANT$ in ISG20L2, rs143224912 in SETDB1 and @VARIANT$ in S100A3, and one novel variant in S100A13, were identified. The ISG20L2 and @GENE$ variants were excluded based on their frequencies in normal population cohorts.",6637284,S100A13;7523,SETDB1;32157,rs3795737;tmVar:rs3795737;VariantGroup:5;CorrespondingGene:81875;RS#:3795737,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In vitro studies revealed that p.Gly221Arg lacked DNA binding, had impaired transactivation activity on the AMH promoter, and failed to bind cofactor @GENE$. Functional testing of three GATA4 variants identified in 46,XY DSD individuals of our study showed similarly disruptive effect for the missense mutation @VARIANT$, but no effect on transactivation activity on the CYP17 promoter for GATA4 variants p.Pro226Leu and pTrp228Cys. While all these variants are conserved across species (Figure 2) and located in the N-terminal zinc finger domain of @GENE$ (Figure 1), only Gly221 and Cys238 are close to Zn binding sites. The @VARIANT$ is not directly involved in Zn binding but is situated next to Cys220 which binds the Zn atom, and therefore, the mutation Gly221Arg will disrupt the Zn binding, leading to a non-functional GATA4.",5893726,FOG2;8008,GATA4;1551,p.Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,Gly221;tmVar:p|Allele|G|221;VariantGroup:4;RS#:398122402(Expired),0
"The other two LRP6 variants, @VARIANT$ (p.Ser817Cys) and c.4333A>G (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the WNT10A mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance. Segregation analysis of the parent-child trio revealed that the father, who was hypodontic, carried all three @GENE$ variants but not the @GENE$ mutation, which was found in the mother.",8621929,LRP6;1747,WNT10A;22525,c.2450C>G;tmVar:c|SUB|C|2450|G;HGVS:c.2450C>G;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"(A) MRI of a 31-year-old woman with compound heterozygous mutations in PKHD1, who received a diagnosis of polycystic kidneys at 17. (B) MRI of a 45-year-old woman, who carried two heterozygous variants in @GENE$, p.(@VARIANT$), and @GENE$, p.(@VARIANT$).",7224062,PKHD1;16336,PMM2;257,His3124Thr;tmVar:p|SUB|H|3124|T;HGVS:p.H3124T;VariantGroup:17;CorrespondingGene:5314,Gly42Arg;tmVar:p|SUB|G|42|R;HGVS:p.G42R;VariantGroup:5;CorrespondingGene:5373;RS#:755402538;CA#:7893895,1
"@GENE$-@VARIANT$ affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, @GENE$-@VARIANT$ is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), @GENE$: c.1063G>A (p.G355R) and @GENE$: @VARIANT$ (p.410T>M), EPHA2: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"20  The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the @GENE$ (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS. 21  @GENE$ promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors.",7689793,CAPN9;38208,TRIP6;37757,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"A single @GENE$ mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The @VARIANT$ frameshifting mutation, and the p.V435I and @VARIANT$ missense mutations result in the absence of a secreted protein. (B) Upper panels: Representative western blots for the phosphorylated and total forms of @GENE$ (left panel) and @GENE$ (right panel) in GN11 cells following a 20 min incubation with serum-free medium (mock, negative control), 100 ng/ml of purified recombinant human Sema3A, or the conditioned media from transfected COS-7 cells producing wild-type or mutated Sema3A proteins.",3426548,FAK;7314,ERK1/2;5595;5594,p.D538fsX31;tmVar:p|FS|D|538||31;HGVS:p.D538fsX31;VariantGroup:12;CorrespondingGene:2260,p.R66W;tmVar:p|SUB|R|66|W;HGVS:p.R66W;VariantGroup:4;CorrespondingGene:10371;RS#:143241978,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"However, neither @VARIANT$ in @GENE$ nor @VARIANT$ in @GENE$ was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).",4998745,GJB2;2975,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, p.Arg896Trp) and @GENE$ (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of @GENE$ in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT5;71688,LQT2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the @GENE$ [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:c.1093G > A; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).                   The PCDH15 variant [NM_033056: c.3101G > A; @VARIANT$] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892).",6053831,PCDH15;23401,USH1G;56113,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,p.(Arg1034His);tmVar:p|SUB|R|1034|H;HGVS:p.R1034H;VariantGroup:2;CorrespondingGene:124590,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::@GENE$ (p.E229K), and @GENE$ (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction.",5953556,CYP1B1;68035,TEK;397,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in @GENE$, PROKR2, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,FGFR1;69065,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"In addition, we found an elevated frequency (8%) of heterozygous and rare PITX2 variants in the group of CG cases who were known to carry @GENE$ glaucoma-associated genotypes, and one of these @GENE$ variants arose de novo. To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: c.535C>A, @VARIANT$) have not been previously identified.",6338360,CYP1B1;68035,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the @GENE$ gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,KCNE2;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, SEC23A c.1200G>C (@VARIANT$) and @GENE$ @VARIANT$ (p.R334C), associated with congenital birth defects in two patients from a consanguineous family. Patients presented with carbohydrate-deficient transferrin, tall stature, obesity, macrocephaly, and maloccluded teeth. The parents were healthy heterozygous carriers for both mutations and an unaffected sibling with tall stature carried the heterozygous mutation in @GENE$ only.",4853519,MAN1B1;5230,SEC23A;4642,p.M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"A novel missense mutation was found in @GENE$ (@VARIANT$, @VARIANT$). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, p.H678R and p.S1067L, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001).",6098846,DUOXA2;57037,DUOX2;9689,c.398G>A;tmVar:c|SUB|G|398|A;HGVS:c.398G>A;VariantGroup:16;CorrespondingGene:4094;RS#:745463507;CA#:4885341,p.R133H;tmVar:p|SUB|R|133|H;HGVS:p.R133H;VariantGroup:16;CorrespondingGene:7038;RS#:745463507;CA#:4885341,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in IMP4 (OMIM 612981; @VARIANT$, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in @GENE$ (OMIM 609890; rs748114415, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and @GENE$ (OMIM 612496; @VARIANT$, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,UBR4;10804,ARHGEF19;17710,rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628,rs144638812;tmVar:rs144638812;VariantGroup:0;CorrespondingGene:128272;RS#:144638812,0
"A PCR amplicon containing GNRHR exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (@VARIANT$), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (@VARIANT$;[=]) (p.Arg80Cys) in the @GENE$ gene.         The @GENE$ frameshift mutation was identified in two different families and has not been reported before.",5527354,PROKR2;16368,GNRHR;350,rs373270328;tmVar:rs373270328;VariantGroup:0;CorrespondingGene:2798;RS#:373270328,c.[238C > T];tmVar:c|SUB|C|238|T;HGVS:c.238C>T;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,0
"However, we did not found any potential disease-related variant on @GENE$ of all 77 cases. @GENE$-c.3035C>T (p.Ala1012Val) variant impaired the negative feedback mechanism of cholesterol synthesize in H293T cell lines SCAP-@VARIANT$ (p.Ala1012Val) variant was introduced into H293T cell lines by CRISPR-Cas9 methodology. After incubated with medium A (as described in the materials and methods section) for 6 hours, the wild-type goups showed a significant different distribution of SREBP-2 in cytoplasm and nucleus, (Figure 4A) while the SCAP-mutated groups shows no such difference (Figure 4B). These phenomenon indicate that the mutated SCAP-c.3035C>T (p.Ala1012Val) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. AGXT2-c.1103C>T (p.Ala338Val) variant impaired the catabolism of ADMA in EA. hy926 cell lines AGXT2-@VARIANT$ (p.Ala338Val) variant was introduced into EA.",5725008,AGXT2;12887,SCAP;8160,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,KAL1;55445,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"Therefore, the finding of both heterozygous and homozygous (or compound heterozygous) KS patients for a given mutation in @GENE$ (e.g., p.R85H or p.L173R, see Table 1) is quite remarkable and raises the question of a possible digenic mode of inheritance in heterozygous patients. In our cohort, none of the patients carrying a mutation in PROKR2 was carrying a mutation in PROK2 too. We did not find a mutation in @GENE$ in any of the individuals carrying a mutation in PROKR2 or PROK2, either. However, one of the patients heterozygous for the @VARIANT$ mutation in PROKR2 (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in KAL1 exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,PROKR2;16368,FGFR1;69065,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0
"One subject was homozygous for SOD1 @VARIANT$ (D90A), while three others carried two mutations in SETX. One subject tested homozygous for @GENE$ p.I2547T, but we did not exclude the possibility of a deletion on one allele. The two additional subjects could each be compound heterozygotes comprised of a rare variant (p.C1554G or p.I2547T with 0.3% and 0.5% MAF in population database respectively) and a novel variant (p.R168Q or p.T14I respectively). The subject carrying p.I2547T and p.T14I was also heterozygous for @GENE$ @VARIANT$ which has previously been reported in a subject with SALS.",4293318,SETX;41003,TAF15;131088,p.D91A;tmVar:p|SUB|D|91|A;HGVS:p.D91A;VariantGroup:54;CorrespondingGene:6647;RS#:80265967;CA#:124296,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in @GENE$ and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G).",3125325,USH2A;66151,CDH23;11142,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2). @GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling.",6161649,SCUBE2;36383,VEGFR2;55639,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and @GENE$ p.R408C with SETX @VARIANT$ and SETX p.T14I).,4293318,VAPB;36163,TAF15;131088,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d). Genotyping analysis revealed that the @GENE$/235delC was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 156 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,0
"All of them had confirmed hypogonadotropic hypogonadism and anosmia or hyposmia, and some already harbored a mutation in one of the five KS genes we had previously analyzed, specifically, in KAL1 (13 patients), @GENE$ (30 patients), FGF8 (3 patients), PROKR2 (30 patients), or PROK2 (12 patients). Nonsynonymous mutations in SEMA3A were found in 24 patients (20 males and 4 females), all in heterozygous state (Table 1). They consist of a frameshifting deletion of 14 nucleotides (c.del1613_1626; p.D538fsX31), and seven different missense mutations (p.R66W, p.N153S, p.I400V, p.V435I, @VARIANT$, p.R730Q, p.R733H) that affect evolutionarily conserved aminoacid residues located in different domains of the protein (Figure 3). In addition, the p.R730Q and @VARIANT$ mutations, which both remove basic residues in the C-terminal basic motif of @GENE$, are predicted to affect in vivo proteolytic processing by furin-like endoproteases at residue R734.",3426548,FGFR1;69065,Sema3A;31358,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.R733H;tmVar:p|SUB|R|733|H;HGVS:p.R733H;VariantGroup:6;CorrespondingGene:10371;RS#:318240753;CA#:220075,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FAT4;14377,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,0
"(A) In addition to c.235delC in GJB2, the de novo variant of @GENE$, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of @GENE$ and a monoallelic @VARIANT$ variant of GJB3.",4998745,MITF;4892,GJB2;2975,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We found that GATA4 variant Cys238Arg lost transcriptional activity (Figure 3) similar to the previously described @VARIANT$ mutant. By contrast, @GENE$ variants @VARIANT$ and Pro226Leu activated the @GENE$ promoter similar to wt.",5893726,GATA4;1551,CYP17;73875,Gly221Arg;tmVar:p|SUB|G|221|R;HGVS:p.G221R;VariantGroup:4;CorrespondingGene:2626;RS#:398122402(Expired),Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in @GENE$ and a heterozygous missense variant @VARIANT$(p.Ala64Thr) in @GENE$ (Table 2).,7549550,MYOD1;7857,MEOX1;3326,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,c.190G>A;tmVar:c|SUB|G|190|A;HGVS:c.190G>A;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; p.Trp275X of @GENE$).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
The @GENE$ variant @VARIANT$ did not show significant protein stability differences with the wild-type protein (Fig 6C and Fig 6D). FOXC2 @VARIANT$ variant decreases protein stability. Time course stability analysis of @GENE$ (A) and PITX2 (C) coding variants found in PCG patients was carried out by transient expression in HEK-293T cells.,6338360,PITX2;55454,FOXC2;21091,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.H395N;tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"These two individuals were heterozygous carriers of @VARIANT$ mutation in ABCC6 and @VARIANT$ in @GENE$. Since heterozygous carriers of p.R1141X in @GENE$ alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be due to digenic inheritance.",2900916,GGCX;639,ABCC6;55559,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG @VARIANT$ with @GENE$ p.M170I and TAF15 p.R408C with SETX p.I2547T and @GENE$ p.T14I).",4293318,VAPB;36163,SETX;41003,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,0
"This analysis indicated that the @GENE$ variant c.1663G>A (rs138172448), which results in a @VARIANT$ change, and the @GENE$ gene variant c.656C>T (rs144901249), which results in a @VARIANT$ change, are both predicted to be damaging.",6180278,CAPN3;52,DES;56469,p.Val555Ile;tmVar:p|SUB|V|555|I;HGVS:p.V555I;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,p.Thr219Ile;tmVar:p|SUB|T|219|I;HGVS:p.T219I;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance.",8152424,CDON;22996,FGFR1;69065,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"A novel variant @GENE$ @VARIANT$ (p.K618R) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (CELSR1 p.Q2924H, @GENE$ p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,SCRIB;44228,CELSR1;7665,c.1853A > G;tmVar:c|SUB|A|1853|G;HGVS:c.1853A>G;VariantGroup:2;CorrespondingGene:5754;RS#:139041676;CA#:3816321,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) @VARIANT$, and the rest were missense variants. However, the possibility of being loss-of-function intolerant (pLI) value of IGSF10 is zero, which means that single heterozygous LoF variant of IGSF10 is not sufficient to cause disease. Furthermore, proband P18 was only detected one heterozygous variant, PROKR2 @VARIANT$, whereas probands @GENE$ and P14 carried the same PROKR2 variant and additional variants in other candidate genes. The families' results consistently support the digenic/oligogenic inheritance in IHH, and novel IHH-associated genes and variants may be elucidated with advances in genetic knowledge (for example, noncoding variants) and genomic technologies (for example, those for detecting complex structural variations). We also found four novel potential candidate genes for future investigations. Of interest, @GENE$ and CDON are known causative genes of PSIS, one of congenital hypopituitarism.",8152424,P12;41339,CCDC88C;18903,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,p. Trp178Ser;tmVar:p|SUB|W|178|S;HGVS:p.W178S;VariantGroup:0;CorrespondingGene:128674;RS#:201835496;CA#:270917,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,SOX10;5055,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"   The substitutions of @VARIANT$ (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of @GENE$ L117F and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f).",7067772,pendrin;20132,ephrin-B2;3019,Leu117 to Phe;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
That may be how @GENE$-@VARIANT$ plays a protective role against the detrimental phenotype induced by the @GENE$-@VARIANT$ mutation.,5426766,SCN5A;22738,CACNA1C;55484,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,1
"Subject R302 was diagnosed as MH negative, so we ruled out a pathogenic role of the @GENE$ @VARIANT$ variant in MH. Subject R462 was diagnosed as MHS, which appeared to correlate with @GENE$ p. R498L, previously reported in a single MHS subject. However, the frequency of this variant in the general population is about 20-fold higher than the frequencies of pathogenic CACNA1S variants associated with MHS. It is also important to note that the diagnostic test for MH has a high false-positive rate of 22%, which raises the possibility that MHS diagnosis in subject R462 may be false. Based on these results, we also ruled out a pathogenic role of the CACNA1S @VARIANT$ variant in MH.",6072915,RYR1;68069,CACNA1S;37257,p.T4823 M;tmVar:p|SUB|T|4823|M;HGVS:p.T4823M;VariantGroup:3;CorrespondingGene:6261;RS#:148540135;CA#:24146,p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0
"A single @GENE$ mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  @GENE$, 23  @GENE$, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS.",7689793,EBNA1BP2;4969,TRIP6;37757,p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The latter individuals were also carriers of the ABCC6 nonsense mutation @VARIANT$. Specifically, the mother and her twin sister were heterozygous for the @GENE$ missense mutation @VARIANT$ and the @GENE$ nonsense mutation p.R1141X, suggesting digenic inheritance of their cutaneous findings.",2900916,GGCX;639,ABCC6;55559,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (@GENE$ c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD6;2617,FZD1;20750,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, @GENE$, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the @GENE$ gene variant [p.(@VARIANT$)].",8446458,ANOS1;55445,DUSP6;55621,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"For HH12, the molecular analysis allowed the identification of a novel variation, c.614_616del; @VARIANT$, in the PROKR2 gene at a heterozygous state. Bioinformatics analysis using the Uniprot database showed that the @VARIANT$ is buried amid the second extracellular loop and that this residue is highly conserved in @GENE$ from mouse, rat, chimp, dog, cow, Xenopus tropicalis, and zebrafish and in the human @GENE$ protein.",8446458,Prokr2;16368,PROKR1;10968,p.(Lys205del);tmVar:p|DEL|205|);HGVS:p.205del);VariantGroup:21;CorrespondingGene:128674,lysine amino acid at position 205;tmVar:|Allele|LYSINEAMINO|205;VariantGroup:11;CorrespondingGene:6939,0
"The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic @VARIANT$ (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Except for the SEMA7A gene variant [p.(@VARIANT$)], mutations identified in DUSP6, ANOS1, @GENE$, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the @GENE$ gene variant [p.(@VARIANT$)].",8446458,DCC;21081,DUSP6;55621,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, @GENE$ p.R769W, DVL3 p.R148Q, PTK7 p.P642R, @GENE$ @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,SCRIB;44228,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,CDH23;11142,MYO7A;219,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"For example, two variants in proband P15, @VARIANT$ in @GENE$ and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother.",8152424,PROKR2;16368,DDB1 and CUL4 associated factor 17;80067;1642,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,1
"The heterozygous @VARIANT$ (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys. Additionally, the monoallelic p.Gly213Ser (c.637G>A) mutation was also detected in exon 3 of @GENE$, it results in the substitution of Gly at residue 213 to Ser. Sequence analyses of her parents' genome revealed that the mutant alleles were from her mother (Fig. 2E), who only had microdontia of the upper lateral incisors. Her father did not carry mutations for either of these genes.     ""S4"" is an 8-year-old boy who also had the typical characteristics and facial features of HED and was missing 28 permanent teeth, but he did not have plantar hyperkeratosis or nail abnormalities (Table 1). The p.Ala349Thr (c.1045G>A) mutation in exon 9 of EDA and heterozygous @VARIANT$ (c.511C>T) mutation in exon 3 of WNT10A were detected.",3842385,EDA;1896,WNT10A;22525,p.Arg156Cys;tmVar:p|SUB|R|156|C;HGVS:p.R156C;VariantGroup:5;CorrespondingGene:1896;RS#:132630313;CA#:255655,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The MFE of @GENE$ p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.           RNA secondary structural prediction. (a, b) Compared with wild-type KCNH2, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A @VARIANT$ mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), @GENE$ p.307_308del showed a decreasing trend in molecular weight and increasing instability.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,CELSR2;1078,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"This phenotypic incomplete penetrance might be modified by SCN5A-@VARIANT$ variant and sex. As shown in Table 3, all male individuals carrying the @GENE$-@VARIANT$ mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant @GENE$-R1193Q showed the ERS phenotypes.",5426766,CACNA1C;55484,SCN5A;22738,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel @VARIANT$ variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
The @VARIANT$ (@VARIANT$) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected.,3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"Mutations in melanocyte inducing transcription factor (@GENE$), coding for a basic helix-loop-helix (BHLH) leucine zipper protein, are known to cause the WS2 phenotype due to defects in survival, proliferation, and migration of melanocytes. The deletion mutation (c.965delA) identified in this study lies in the BHLH domain and predicted to cause frameshift (p.Asn322fs) and stop codon seven amino acids downstream (@VARIANT$). The missense variant (@VARIANT$) in the @GENE$ gene changes the conserved amino acid Valine to Glycine (p.Val34Gly).",7877624,MITF;4892,C2orf74;49849,Asn322Metfs*7;tmVar:p|FS|N|322|M|7;HGVS:p.N322MfsX7;VariantGroup:3;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3). In vitro evidence of these @GENE$ mutations included reduced protein expression and splicing defects.,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"@GENE$-p.K897T was previously associated with a prolonged QT interval in several different populations and can alter the biophysical properties of mutant channels (current density, activation, inactivation, and recovery from inactivation) and exacerbate the IKr reduction caused by other KCNH2 mutations. KCNH2-p.K897T affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, KCNE1-p.G38S is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia. Nevertheless, in vitro studies demonstrated that the KCNE1-p.G38S variant causes only a mild reduction of the delayed rectifier K+ currents. Therefore, G38S could be a genetic modifier, but the evidence available does not suggest it has an overt effect on the function of the KCNQ1 and KCNH2 channels. Given the complexity of the LQTS-related genetic background in our family, we functionally characterized only KCNH2-p.C108Y and @GENE$-@VARIANT$. Our data demonstrate that the activity of KCNH2-@VARIANT$ was significantly lower than that of the wild type.",5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Our investigations revealed 12 rare heterozygous missense mutations in @GENE$ by targeted sequencing. Interestingly, four of these TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families.",5953556,TEK;397,CYP1B1;68035,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"Our results indicate that the novel KCNH2-@VARIANT$ variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, @GENE$-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNH2;201,KCNE1;3753,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Pedigree and sequence chromatograms of the patient with the p.Ala771Ser in MYO7A and @VARIANT$ in PCDH15 mutations. (A) The pedigree and sequence results of the proband and family. (B) Sequence chromatograms from wild-type and mutations. The proband, his mothor and one brother carried a heterozygous 2311G>T transition in exon 20, which results in an alanine to a serine (@VARIANT$) in @GENE$. Another variation, 158-1G>A in intron 3 of @GENE$, was derived from the proband and his father.",3949687,MYO7A;219,PCDH15;23401,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,0
"Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)@VARIANT$, and @GENE$ c.1664-2A>C, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model. One unreported and probably deleterious missense variant @VARIANT$ of another PSIS gene, CDON, was also found in case P17 who carried a missense variant in CHD7, a causative gene of IHH. @GENE$ seems to act similarly as CCDC88C through a digenic/oligogenic model to contribute to IHH.",8152424,FGFR1;69065,CDON;22996,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Val969Ile;tmVar:p|SUB|V|969|I;HGVS:p.V969I;VariantGroup:13;CorrespondingGene:50937;RS#:201012847;CA#:3044125,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (@VARIANT$) in @GENE$ were identified. The proband's father with the SLC20A2 @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0
"The @VARIANT$ and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and @GENE$ @VARIANT$), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants @VARIANT$; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR2;1078,FAT4;14377,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,0
"Patient P0432 has a @VARIANT$ (@VARIANT$) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and @GENE$ (c.9921T>G).",3125325,CDH23;11142,USH2A;66151,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,0
"  Digenic inheritances of @GENE$/@GENE$ and GJB2/GJB3 (group II). (A) In addition to c.235delC in GJB2, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus. (C) The sequence of the p.R341C variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3.",4998745,GJB2;2975,MITF;4892,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother. Proband 17 inherited @GENE$ p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,PROKR2;16368,CHD7;19067,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"The @VARIANT$ (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of @VARIANT$. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the @GENE$ gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein. However, the two rare FUS variants (@VARIANT$ and P106L) that were detected in this study were located in the N-terminal ""prion-like"" Q/G/S/Y domain (amino acids 1-165) of the protein.",6707335,SPG11;41614,FUS;2521,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,Y25C;tmVar:p|SUB|Y|25|C;HGVS:p.Y25C;VariantGroup:12;CorrespondingGene:2521;RS#:141516414;CA#:8023442,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, PROK2, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,FGFR1;69065,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in GFI1 and @GENE$. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in @GENE$ (@VARIANT$/c.1145A > G) and MYO6 (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,MYO6;56417,GFI1;3854,p.N382S;tmVar:p|SUB|N|382|S;HGVS:p.N382S;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"  Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (@VARIANT$); P1, P2: thyrotropin >100 microU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (@VARIANT$) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred. Conclusion: This is a report of digenic mutations in @GENE$ and DUOX2 in association with CH, and we hypothesize that the inability of DUOX1 to compensate for @GENE$ deficiency in this kindred may underlie the severe CH phenotype.",5587079,DUOX1;68136,DUOX2;9689,p.R434*;tmVar:p|SUB|R|434|*;HGVS:p.R434*;VariantGroup:0;CorrespondingGene:50506;RS#:119472026,c.1823-1G>C;tmVar:c|SUB|G|1823-1|C;HGVS:c.1823-1G>C;VariantGroup:17;CorrespondingGene:53905,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,REEP4;11888,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A Using whole-exome sequencing, we identified homozygous mutations in two unlinked genes, SEC23A c.1200G>C (@VARIANT$) and @GENE$ c.1000C>T (@VARIANT$), associated with congenital birth defects in two patients from a consanguineous family. Patients presented with carbohydrate-deficient transferrin, tall stature, obesity, macrocephaly, and maloccluded teeth. The parents were healthy heterozygous carriers for both mutations and an unaffected sibling with tall stature carried the heterozygous mutation in @GENE$ only.",4853519,MAN1B1;5230,SEC23A;4642,p.M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,p.R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,UBQLN2;81830,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and @VARIANT$ in MYO7A, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.5749G>T;tmVar:c|SUB|G|5749|T;HGVS:c.5749G>T;VariantGroup:155;CorrespondingGene:4647;RS#:780609120;CA#:224854968,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"There is a splicing site mutation c.1339 + 3A>T in COL4A5, inherited from her mother and a missense mutation @VARIANT$ (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,c.4421C > T;tmVar:c|SUB|C|4421|T;HGVS:c.4421C>T;VariantGroup:14;CorrespondingGene:1286;RS#:201615111;CA#:2144174,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX @VARIANT$ and @GENE$ @VARIANT$).,4293318,ANG;74385,SETX;41003,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"Since @GENE$-@VARIANT$ had not previously been reported, we considered it to be a variant of uncertain clinical significance. Genetic screening of the KCNH2 gene also revealed the KCNH2-c.A2690C (p.K897T) common variant (MAF = 0.187). This variant was previously reported to be a possible negative modifier of IKr that is able to alter channel kinetics, predispose to arrhythmic events, affect the repolarization process, and alter the length of the QT interval. Another common variant in the @GENE$ gene (@VARIANT$) results in the substitution of the glycine residue with serine at position 38 (p.G38S) and is located in the C-terminal cytoplasmic domain.",5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,c.G112A;tmVar:c|SUB|G|112|A;HGVS:c.112G>A;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,KCNH2;201,LQT6;71688,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"The other two @GENE$ variants, c.2450C>G (@VARIANT$) and c.4333A>G (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the @GENE$ mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance.",8621929,LRP6;1747,WNT10A;22525,p.Ser817Cys;tmVar:p|SUB|S|817|C;HGVS:p.S817C;VariantGroup:2;CorrespondingGene:4040;RS#:2302686;CA#:6455462,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (@GENE$) @VARIANT$, and the rest were missense variants.",8152424,CCDC88C;18903,IGSF10;18712,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,0
"We identified a novel compound heterozygous variant in @GENE$ c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; @VARIANT$); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS1;11641,BBS2;12122,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
" Finally, a subject with the heterozygous @VARIANT$ mutation in GJB2 (SH60-136) carried a @VARIANT$ variant in Wolfram syndrome 1 (WFS1) (NM_001145853) according to TES. However, neither p.R143W in @GENE$ nor p.D771N in @GENE$ was predicted to contribute to SNHL of SH60-136 based on rigorous segregation analysis of the phenotype and the variants (Figure 3).",4998745,GJB2;2975,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Under these conditions, co-expression of EphA2 did not affect protein expression levels of these pathogenic forms of pendrin (Fig. 5a) but partially restored membrane localization of myc-pendrin @VARIANT$, L445W or Q446R (Supplementary Fig. 5a, b). On the other hand, @GENE$ overexpression did not affect localization of G672E.    The substitutions of Leu117 to Phe (L117F), Ser166 to Asn (S166N), and Phe335 to Leu (F335L), identified in Pendred syndrome patients, do not affect their membrane localization. Given the reported normal function of pendrin @VARIANT$ and pendrin S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, @GENE$ S166N, and pendrin F355L mutations on EphA2 interaction and internalization was examined.",7067772,EphA2;20929,pendrin;20132,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
"The results showed that, in addition to the @GENE$ gene variant [p.(@VARIANT$)], a second variant in @VARIANT$ in the CCDC141 gene was involved in the second highest number of pathogenic digenic combinations (15%), with 18 other variants in 13 genes. The @GENE$ variant was found at a homozygous state in the patient HH1 and at a heterozygous state in the asymptomatic cases.",8446458,PROKR2;16368,CCDC141;52149,Pro290Ser;tmVar:p|SUB|P|290|S;HGVS:p.P290S;VariantGroup:0;CorrespondingGene:128674;RS#:149992595;CA#:9754257,c.2803C > T;tmVar:c|SUB|C|2803|T;HGVS:c.2803C>T;VariantGroup:4;CorrespondingGene:285025;RS#:17362588;CA#:2006885,0
"The other two @GENE$ variants, c.2450C>G (p.Ser817Cys) and c.4333A>G (@VARIANT$), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the @GENE$ mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance.",8621929,LRP6;1747,WNT10A;22525,p.Met1445Val;tmVar:p|SUB|M|1445|V;HGVS:p.M1445V;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and @GENE$/TACR3 (@VARIANT$ of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,KAL1;55445,NELF;10648,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Circles, female; squares, male; gray, TNFRSF13B/TACI C104R mutation; blue @GENE$ @VARIANT$ mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/@GENE$ @VARIANT$ mutations.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"GJB2 Single Heterozygotes where DFNB1 was Excluded as a Final Molecular Diagnosis: A Fortuitously Detected @GENE$ Mutation (Group I) There were three subjects (SH166-367, SH170-377, and SB175-334) with two recessive mutations, presumed to be pathogenic, in completely different deafness genes. One of the children with a heterozygous @VARIANT$ mutation (SH 166-367) was identified to carry a predominant founder mutation, p.R34X (c.100C>T) (@VARIANT$), and a novel variant, p.W482R of Transmembrane channel-like 1 (@GENE$) (NM_138691), in a trans configuration (Table 1).",4998745,GJB2;2975,TMC1;23670,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,rs121908073;tmVar:rs121908073;VariantGroup:11;CorrespondingGene:117531;RS#:121908073,1
"Four genes (including @GENE$, ZFHX3, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-@VARIANT$ (p.Ala1012Val) and AGXT2-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,AGXT2;12887,SCAP;8160,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The @GENE$ and SETDB1 variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in @GENE$ (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
"The p.Ile312Met (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of @GENE$ showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys.",3842385,WNT10A;22525,EDA;1896,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Co-segregation of TEK @VARIANT$ and @GENE$ @VARIANT$ was observed in two pedigrees and only a representative pedigree is shown. b Chromatograms of the four probands (lower panel) harboring the four different heterozygous @GENE$ mutations.,5953556,CYP1B1;68035,TEK;397,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"In addition, 2 genes presented variants in 3 patients: @GENE$ (patients 6, 7 and 8) and @GENE$ (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,MAML3;41284,NOTCH1;32049,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and @GENE$ (@VARIANT$).",3125325,CDH23;11142,USH2A;66151,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (@GENE$ @VARIANT$ with VAPB p.M170I and TAF15 p.R408C with SETX @VARIANT$ and @GENE$ p.T14I).,4293318,ANG;74385,SETX;41003,p.K41I;tmVar:p|SUB|K|41|I;HGVS:p.K41I;VariantGroup:28;CorrespondingGene:283;RS#:1219381953,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 @VARIANT$), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,PRICKLE4;22752,CELSR1;7665,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,c.3800A>G;tmVar:c|SUB|A|3800|G;HGVS:c.3800A>G;VariantGroup:2;CorrespondingGene:1952;RS#:373263457;CA#:4677776,0
"The presence of concomitant mutations, such as the @GENE$ T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the TCF3 T168fsX191 mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the @GENE$/TACI C104R mutation has a modifying effect on the phenotype and is relatively benign in this family. Hence, priority should be given to identifying the TCF3 @VARIANT$ mutation for preimplantation genetic diagnosis and/or chorionic villus sampling. Based on both clinical and laboratory quantification, it appears neither the TNFRSF13B/TACI @VARIANT$ mutation nor the TCF3 T168fsX191 mutation alone is sufficient to cause the complete, severe CVID-like disorder and SLE observed in the proband.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"20  The identified CUX1 (NM_001202543: c.1438A > G, @VARIANT$) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, @VARIANT$) and the @GENE$ (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,TRIP6;37757,CAPN9;38208,p.Ser480Gly;tmVar:p|SUB|S|480|G;HGVS:p.S480G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"Based on these results, we assume that the @GENE$ @VARIANT$ variant is more frequent in the Hungarian population (both in patients and controls) than in other populations, although further large cohort studies are needed to confirm this conclusion. This study provides additional evidence that NEK1 missense variants may contribute to the development of sALS.    Missense variants in the @GENE$ gene were detected in four patients: the T338I variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene.",6707335,NEK1;14376,NEFH;40755,R261H;tmVar:p|SUB|R|261|H;HGVS:p.R261H;VariantGroup:2;CorrespondingGene:4750;RS#:200161705;CA#:203762,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Sequence alterations were detected in the @GENE$ (rs144651558), RYR1 (@VARIANT$), @GENE$ (rs138172448), and DES (@VARIANT$) genes.",6180278,COL6A3;37917,CAPN3;52,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the @GENE$ protein (c.229C>T; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in @GENE$. Mutation name is based on the full-length S100A3 (NM_002960) and S100A13 (NM_001024210) transcripts.    Exome sequencing Initially, WES was performed in the proband of Family 1A (F1:IV-1) (figure 1a). After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in ISG20L2, rs143224912 in SETDB1 and @VARIANT$ in S100A3, and one novel variant in S100A13, were identified.",6637284,S100A3;2223,S100A13;7523,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Rare CTRC genotypes contributed to the development of ICP in 4.3% of cases  CTRC has conventionally been regarded as being the least important gene in terms of a genetic predisposition to chronic pancreatitis, as compared with @GENE$ and SPINK1. This view received further support from two recent developments. First, some of the CTRC variants characterized by a complete or virtually complete functional loss of the affected alleles, exemplified by p.K247_R254del and @VARIANT$, have been reported in unrelated healthy controls. Second, whereas a heterozygous CTRC whole gene deletion was found in trans with other genetic predisposing alleles in two subjects with familial chronic pancreatitis, a different homozygous CTRC whole gene deletion was identified in a patient with asymptomatic ICP. Employing the functionally null CTRC allele, p.K247_R254del, which increases the risk of ICP 6.4-fold, as a reference (N.B. the heterozygous SPINK1 @VARIANT$ allele confers a >10-fold increased risk), any loss-of-function variants in the @GENE$ gene may at most be interpreted as disease-predisposing.",3738529,PRSS1;134623,CTRC;21422,p. G217S;tmVar:p|SUB|G|217|S;HGVS:p.G217S;VariantGroup:18;CorrespondingGene:11330;RS#:202058123;CA#:613437,p. N34S;tmVar:p|SUB|N|34|S;HGVS:p.N34S;VariantGroup:7;CorrespondingGene:6690;RS#:17107315;CA#:123440,0
"        Molecular Data All three probands carry two heterozygous variants: @GENE$, c.1175C>T (@VARIANT$), and TIA1, c.1070A>G (@VARIANT$). None of the unaffected family members harbor both variants (Figure 1). The @GENE$ variant and SQSTM1 variants have been reported in multiple databases.",5868303,SQSTM1;31202,TIA1;20692,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"Variant @GENE$-@VARIANT$ results in the non-conservative substitution of arginine with histidine at position 583 (p.R583H) located within the C-terminal domain. Since this variant was previously reported in LQTS patients and is rare in the general population (minor allele frequency (MAF) of 0.000016 in the Exome Aggregation Consortium (ExAC) database), it was initially considered a likely pathogenic mutation. Variant @GENE$-@VARIANT$ causes the replacement of a cysteine residue by tyrosine (p.C108Y) within the N-terminal PAS (Per-Arnt-Sim) domain.",5578023,KCNQ1;85014,KCNH2;201,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ @VARIANT$ and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-@GENE$ @VARIANT$ with GFP-CYP1B1 E229 K as compared to WT proteins (Fig. 2).",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"Two of these variants were in genes implicated in heart development and cardiac pathology, @GENE$ and @GENE$ (Table 4). The two variants chr18:77170979 G>A for NFATC1 and chr1:228462101 G>A for OBSCN lead to novel missense variants, @VARIANT$ and @VARIANT$ respectively.",5611365,NFATC1;32336,OBSCN;70869,p.R222Q;tmVar:p|SUB|R|222|Q;HGVS:p.R222Q;VariantGroup:10;CorrespondingGene:4772;RS#:1390597692,p.C1880Y;tmVar:p|SUB|C|1880|Y;HGVS:p.C1880Y;VariantGroup:129;CorrespondingGene:84033,1
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), @GENE$ (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,REEP4;11888,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations. The TEK @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and @GENE$ genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT6;71688,KCNH2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
" @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"(C) Sanger sequencing confirmed a homozygous in-frame deletion (@VARIANT$) in @GENE$ gene and a homozygous splice-donor mutation (@VARIANT$) in CARD9 gene. (D) Western Blot of CARD9 and MYD88 proteins performed on PBMC, EBVB, and PHA derived T cell lines. (E) TNFalpha production by monocytes after LPS stimulation (mean +- SEM of n = 2). (F) Phenotypic analysis of iDC and @GENE$ differentiated in vitro.",6383679,MYD88;1849,mDC;7529,c.195_197delGGA;tmVar:p|DEL|195_197|G;HGVS:p.195_197delG;VariantGroup:2;CorrespondingGene:4615,c.1434+1G>C;tmVar:c|SUB|G|1434+1|C;HGVS:c.1434+1G>C;VariantGroup:0;CorrespondingGene:64170;RS#:141992399;CA#:500026,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (@GENE$). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6. Genetic screening revealed that both sons are not carrying the familial @GENE$ mutation.",6610752,LQT6;71688,KCNH2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: @VARIANT$ (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: c.1229C>A (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1300G>A;tmVar:c|SUB|G|1300|A;HGVS:c.1300G>A;VariantGroup:1;CorrespondingGene:5172;RS#:757552791;CA#:4432772,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"In Vitro Functional Studies of Novel GATA4 Variants To test the transcriptional activity of identified GATA4 variants, we constructed mammalian expression vectors of wt and mutant GATA4 and tested them on three different promoters that have been described being regulated by GATA4, namely the @GENE$, @GENE$, and CYP17 promoters. For these studies, we used different cell systems (HEK293, NCI-H295R, and JEG3), but found that only JEG3 cells transfected with the CYP17 promoter revealed consistent results for comparing wt to mutant GATA4. We found that GATA4 variant @VARIANT$ lost transcriptional activity (Figure 3) similar to the previously described Gly221Arg mutant. By contrast, GATA4 variants @VARIANT$ and Pro226Leu activated the CYP17 promoter similar to wt.",5893726,AMH;68060,SRY;48168,Cys238Arg;tmVar:p|SUB|C|238|R;HGVS:p.C238R;VariantGroup:0;CorrespondingGene:2626,Trp228Cys;tmVar:p|SUB|W|228|C;HGVS:p.W228C;VariantGroup:3;CorrespondingGene:4038,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Mutagenesis Sequence variants KCNH2-@VARIANT$ (p.C108Y) and KCNQ1-@VARIANT$ (p.R583H) were introduced into KCNH2 and @GENE$ cDNAs, respectively, as described previously. Primers used for mutagenesis are available upon request. The KCNH2-WT, KCNQ1-WT, and mutant coding sequences were engineered in bicistronic mammalian vectors pIRES2-EGFP (Biosciences-Clontech, Palo Alto, CA, USA). In addition, KCNH2-WT and @GENE$-WT were cloned in pIRES2-DsRed for co-expression experiments.",5578023,KCNQ1;85014,KCNE1;3753,c.G323A;tmVar:c|SUB|G|323|A;HGVS:c.323G>A;VariantGroup:3;CorrespondingGene:3757,c.G1748A;tmVar:c|SUB|G|1748|A;HGVS:c.1748G>A;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,0
"In patient AVM226, we identified the compound heterozygous variants c.3775G>A (@VARIANT$) and c.2966A>T (@VARIANT$) in DSCAM (table 2). @GENE$ and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.",6161649,DSCAML1;79549,DSCAM;74393,p.Val1259Ile;tmVar:p|SUB|V|1259|I;HGVS:p.V1259I;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,p.Gln989Leu;tmVar:p|SUB|Q|989|L;HGVS:p.Q989L;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and G4290R) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, @VARIANT$), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg37Trp;tmVar:p|SUB|R|37|W;HGVS:p.R37W;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,0
"In the subject III.1, the variant, carried in the heterozygous status, is the @VARIANT$; p.Glu290*, in the glucokinase (@GENE$) gene; the III.2 subject carried the c.872 C > G; @VARIANT$, in the @GENE$ gene.",8306687,CGK;55964,HNF1A;459,c.868 G > T;tmVar:c|SUB|G|868|T;HGVS:c.868G>T;VariantGroup:5;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, @VARIANT$, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in USH2A.",3125325,MYO7A;219,USH1C;77476,c.1556G>A;tmVar:c|SUB|G|1556|A;HGVS:c.1556G>A;VariantGroup:9;CorrespondingGene:4647;RS#:111033206;CA#:278629,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"M3, @GENE$: p.(E173*). M4, PITX2: @VARIANT$. M5, @GENE$: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 @VARIANT$ and @GENE$ p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo @GENE$ c.1664-2A>C variant.",8152424,CDON;22996,FGFR1;69065,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ @VARIANT$ and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-TEK Q214P, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-@GENE$ @VARIANT$ (~70%).",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"In one individual, a variant in @GENE$ has been also observed in addition to the @GENE$ variant. This variant in SMAD1 was classified as VUS. He suffered with PAH associated with a non-repaired atrial septal defect. The variant observed in TBX4 is a very infrequent variant with an extremely low frequency in the analyzed control populations (gnomAD exomes: 0.0000281, gnomAD genomes, 1000G, Kaviar, Beacon, ESP, and Bravo) although the majority of the in silico bioinformatic tools did not suggest a deleterious effect of the variant. Thus, the relationship of the variant detected in SMAD1 and the phenotype of the patients remains unclear. The nonsense TBX4 variant detected in this patient (TBX4(NM_018488.3):@VARIANT$:(@VARIANT$)) was reported last year by Galambos et al.. In their study, the two siblings in whom the same variant was detected presented a clinically specific phenotype with transient patent ductus arteriosus, a patent foramen oval, and interstitial lung disease (ILD).",7650688,SMAD1;21196,TBX4;7968,c.1018C>T;tmVar:c|SUB|C|1018|T;HGVS:c.1018C>T;VariantGroup:19;RS#:765803456,p.Arg340*;tmVar:p|SUB|R|340|*;HGVS:p.R340*;VariantGroup:11;CorrespondingGene:4086,0
"A novel variant @GENE$ c.1853A > G (p.K618R) was not found in the dbSNP database, 1000 genome data, or ExAC database, while the other 10 variants were found with a minor allele frequency lower than 0.0005 in the ExAC population database, or a minor allele frequency of lower than 0.01 in the 1000 genome data of Han Chinese population in Beijing. The alternative allele frequencies of these variants in 510 NTD cases were all lower than 0.01. Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 p.R148Q, PTK7 p.P642R, SCRIB p.G1108E, SCRIB @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (@GENE$ p.Q2924H, CELSR1 @VARIANT$ and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,SCRIB;44228,CELSR1;7665,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,p.R1057C;tmVar:p|SUB|R|1057|C;HGVS:p.R1057C;VariantGroup:7;CorrespondingGene:9620;RS#:148349145;CA#:10295078,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, @VARIANT$), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,TOR2A;25260,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"RNA secondary structure of @GENE$ @VARIANT$ showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Nav1.5 protein property, @GENE$ @VARIANT$ slightly increased the molecular weight and aliphatic index but reduced the instability index.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,gap junction protein beta 6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$).",5887939,CELSR1;7665,DVL3;20928,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ FLNB and @VARIANT$ OFD1 (figure 3D).  @GENE$ and @GENE$ variants in individuals with AIS. (A) Pedigree of AIS twins.",7279190,FLNB;37480,OFD1;2677,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"    CSS170323 carries a heterozygous missense variant @VARIANT$(p.Met210Ile) in MYOD1 and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by MYOD1 (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of @GENE$-mediated pathway.",7549550,MEOX1;3326,TBX6;3389,c.630G>C;tmVar:c|SUB|G|630|C;HGVS:c.630G>C;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,1
"Patient 3 was found to harbor a previously reported p.Arg84His variant in NR5A1, alongside a rare variant in @GENE$ (@VARIANT$, p.Met703Leu, rs121908603:A>C), which has been previously reported in individuals with a diaphragmatic hernia 9 (Bleyl et al., 2007) (Table 3). We also identified a monoallelic change in @GENE$ (@VARIANT$, p.Arg227Gln, rs9332964:G>A) in Patient 11, who also harbored a single codon deletion at position 372 of NR5A1 (Table 3).",5765430,ZFPM2;8008,SRD5A2;37292,c.A2107C;tmVar:c|SUB|A|2107|C;HGVS:c.2107A>C;VariantGroup:3;CorrespondingGene:23414;RS#:121908603;CA#:117963,c.G680A;tmVar:c|SUB|G|680|A;HGVS:c.680G>A;VariantGroup:0;CorrespondingGene:6716;RS#:543895681;CA#:5235442,0
"Circles, female; squares, male; gray, @GENE$/TACI C104R mutation; blue TCF3 T168fsX191 mutation (as indicated). The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/TACI C104R mutations are shown. CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of @GENE$ and @VARIANT$ (c.310T>C) mutation of TACI gene in the proband II.2.",5671988,TNFRSF13B;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in @GENE$ (@VARIANT$), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G).",3125325,CDH23;11142,MYO7A;219,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,0
"The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes. (A) The @GENE$ mutation c.769G>C and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,WNT10A;22525,EDA;1896,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"She inherited c.235delC of @GENE$ from her father and did not have any known large genomic deletions within the DFNB1 locus (Figure 4B). The @VARIANT$ residue of MITF is a well-conserved sequence among species, including zebrafish and tunicates (Figure 4C). Moreover, this MITF variant was not detected in the 666 control chromosomes from normal hearing Korean subjects, supporting the pathogenic potential of p.R341C in MITF in SH107-225. However, symptoms and signs suggesting Waardenburg syndrome type2 (WS2) including retinal abnormalities and pigmentation abnormalities could not be determined due of the patients' young ages.   Digenic inheritances of GJB2/MITF and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, p.R341C was identified in SH107-225. (B) There was no @GENE$ large deletion within the DFNB1 locus.",4998745,GJB2;2975,GJB6;4936,p.R341;tmVar:p|Allele|R|341;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,0
"@GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,SCUBE2;36383,TIMP3;36322,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,RASA1;2168,TIMP3;36322,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,1
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and @GENE$ mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK @VARIANT$ (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS @VARIANT$ mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.P525L;tmVar:p|SUB|P|525|L;HGVS:p.P525L;VariantGroup:62;CorrespondingGene:2521;RS#:886041390;CA#:10603390,0
"Five anencephaly cases carried rare or novel @GENE$ missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB @VARIANT$). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare @GENE$ missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,CELSR2;1078,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and @GENE$ and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated PTPN11 mutation (c.1403 C > T; @VARIANT$) and a novel, potentially pathogenic missense @GENE$ variant (c.1018 C > T; @VARIANT$) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,neurofibromatosis 1;226,SOS1;4117,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,TARDBP;7221,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"In the individual carrying the @VARIANT$ @GENE$ variant, an additional novel alteration (@VARIANT$) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense @GENE$ variants are also linked to the pathogenesis of ALS.",6707335,NEFH;40755,GRN;1577,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,C335R;tmVar:p|SUB|C|335|R;HGVS:p.C335R;VariantGroup:29;CorrespondingGene:29110;RS#:1383907519,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: @VARIANT$, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,@GENE$,CAPN11,VPS13C,@GENE$,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,TRPV4;11003,UNC13B;31376,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in @GENE$ in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes.",6565573,COL4A3;68033,COL4A4;20071,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,1
"C108Y Variants To investigate the functional consequences of @GENE$-@VARIANT$ and @GENE$-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,1
"Moreover, patients carrying a @GENE$ Pro943Leu mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in @GENE$ (@VARIANT$) and MYBPC3 (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYH7;68044,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,0
"Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-@VARIANT$ and @GENE$-@VARIANT$. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. Conclusions A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced @GENE$ protein levels and produced kidney cysts.",5954460,COL4A5;133559,Lama5;4060,p.Pro1243Leu;tmVar:p|SUB|P|1243|L;HGVS:p.P1243L;VariantGroup:2;CorrespondingGene:3911;RS#:756101090;CA#:9942875,p.Asp654Tyr;tmVar:p|SUB|D|654|Y;HGVS:p.D654Y;VariantGroup:4;CorrespondingGene:1287;RS#:1131692060,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We observed that isoproterenol could enhance the activity of LTCC in the HEK293T cells, which may be associated with the evocation of cAMP/protein kinase A pathways by the activation of the endogenous @GENE$ adrenoreceptors. In summary, we investigated an extremely rare large ERS family with a high incidence of nocturnal SCD, in which we found a pathogenic mutation in @GENE$ (@VARIANT$) with loss-of-function. The penetrance was also incomplete, which was modified by a gain-of-functional SCN5A-@VARIANT$ variant and sex.",5426766,beta2;4257,CACNA1C;55484,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, @VARIANT$ in USH1C, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.238_239dupC;tmVar:c|DUP|238_239|C|;HGVS:c.238_239dupC;VariantGroup:241;CorrespondingGene:4647,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, @VARIANT$), @GENE$ (NM_018328.4, c.2000T>G, @VARIANT$), and NRXN1 (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,MBD5;81861,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,p.Leu667Trp;tmVar:p|SUB|L|667|W;HGVS:p.L667W;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0
"During mesoderm development, the expression of MEOX1 is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.   CSS161458 had a heterozygous splicing variant @VARIANT$ in @GENE$, as described above, and a heterozygous missense variant c.464G>T(@VARIANT$) in MYOD1 was also identified.",7549550,MYOD1;7857,RIPPLY1;138181,c.156-1G>C;tmVar:c|SUB|G|156-1|C;HGVS:c.156-1G>C;VariantGroup:12;CorrespondingGene:92129,p.Arg155Leu;tmVar:p|SUB|R|155|L;HGVS:p.R155L;VariantGroup:2;CorrespondingGene:4654;RS#:757176822;CA#:5906444,0
"25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the @GENE$ (NM_003302: c.822G > C, @VARIANT$) and the @GENE$ (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS.",7689793,TRIP6;37757,CAPN9;38208,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"Mutations in genes involved in WNT/beta-catenin signaling, including @GENE$ @GENE$, WNT10B, LRP6, and KREMEN1, are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with LRP6 pathogenic mutations: p.(Gln1252*), p.(@VARIANT$), @VARIANT$, and p.(Asn1075Ser).",8621929,AXIN2;3420,WNT10A;22525,Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.(Ala754Pro);tmVar:p|SUB|A|754|P;HGVS:p.A754P;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"In silico analyses (figure 3C) indicated that the @VARIANT$ residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between p.R2003H FLNB and @VARIANT$ @GENE$ (figure 3D).  FLNB and OFD1 variants in individuals with AIS. (A) Pedigree of AIS twins. Case 98-73 (proband) is indicated with an arrow. (B) Protein sequences around @GENE$. p.R2003 in 11 species.",7279190,OFD1;2677,FLNB;37480,R2003;tmVar:R2003;VariantGroup:29;CorrespondingGene:2317,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic. However, the proband, who carried the two variants, exhibited characteristics of PFBC at an early age, including extensive brain calcification and severe migraines. Therefore, the brain calcification in the proband might have primarily resulted from the @GENE$ mutation and secondarily from the @GENE$ variant.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance.",6707335,CCNF;1335,ALS2;23264,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"Moreover, given the complex association of LQTS mutants in the individuals of the family and the potential causative role of each mutation, and also based on in silico analysis and on evidence from previous studies, we focused on the in vitro functional characterization of the KCNQ1-@VARIANT$ and KCNH2-p.C108Y variants. 2.3. Functional Consequences of the @GENE$-p.R583H and KCNH2-p.C108Y Variants To investigate the functional consequences of KCNQ1-p.R583H and @GENE$-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for REEP4 @VARIANT$. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of Arg37 among vertebrates                TOR2A missense variant A @GENE$ nonsynonymous SNV (@VARIANT$ [NM_130459.3], p.Arg190Cys [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,BSP+;3644,TOR2A;25260,c.109C>T;tmVar:c|SUB|C|109|T;HGVS:c.109C>T;VariantGroup:10;CorrespondingGene:80346;RS#:780399718;CA#:4663211,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"Interestingly, from our cohort with specific clinical manifestations, which was not large in size, we identified two recurrent variants, @GENE$ @VARIANT$ and @GENE$ @VARIANT$, which are rare variants in the general population.",7463850,GRIN2A;645,PLXNB2;66630,c.28C > A;tmVar:c|SUB|C|28|A;HGVS:c.28C>A;VariantGroup:0;CorrespondingGene:2903,c.742C > T;tmVar:c|SUB|C|742|T;HGVS:c.742C>T;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"c.223 - 4C > A might affect the normal splicing of exons in the PROK2 gene, and the novel variant c.306G > C (@VARIANT$) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a @GENE$ gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the PROKR2 gene were found in eight patients. c.337 T > C (@VARIANT$) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. c.491G > A (p. Arg164Gln) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors. The hot spot variant c.533G > C (p. Trp178Ser) was found in six patients and located in the transmembrane domain of the protein, which could significantly reduce the release of ionized calcium and the signal activity.                             The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the FGF/@GENE$ signalling pathway.",8796337,PROK2;9268,FGFR1;69065,p. Arg102Ser;tmVar:p|SUB|R|102|S;HGVS:p.R102S;VariantGroup:20;CorrespondingGene:3730,p. Tyr113His;tmVar:p|SUB|Y|113|H;HGVS:p.Y113H;VariantGroup:0;CorrespondingGene:128674;RS#:202203360;CA#:9754374,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), @GENE$ (rs143445685), @GENE$ (@VARIANT$), and DES (@VARIANT$) genes.",6180278,RYR1;68069,CAPN3;52,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"    A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, @VARIANT$; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,SNAI2;31127,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(@VARIANT$), and a second variant in PKD2, p.(Arg872Gly). Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(Ser872Gly) variant in @GENE$, while only one fetus inherited the p.(@VARIANT$) @GENE$ variant.",7224062,PKD1;250,PKD2;20104,Ser123Thr;tmVar:p|SUB|S|123|T;HGVS:p.S123T;VariantGroup:0;CorrespondingGene:5310;RS#:748717453;CA#:7833716,Arg872Gly;tmVar:p|SUB|R|872|G;HGVS:p.R872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061;CA#:3004303,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in @GENE$, carrying the @VARIANT$ nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1.",4470809,TBK1;22742,OPTN;11085,p.Q235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
"Sequence alterations were detected in the COL6A3 (rs144651558), @GENE$ (@VARIANT$), CAPN3 (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,RYR1;68069,DES;56469,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Three cases of digenic inheritance of USH1 have been reported so far, all caused by mutations in @GENE$ and @GENE$, in agreement with the contribution of cadherin-23 and protocadherin-15 to the hair bundle transient lateral links and tip-links. The pathogenicity of the p.T1209A mutation in CDH23  is, however, questionable since we found it in five alleles from the control population. The c.5601delAAC mutation in PCDH15, leading to an in frame-deletion of a threonine residue (p.T1868del) within the intracellular domain of the protocadherin-15 CD1 isoform, also warrants a special mention. Three protocadherin-15 isoforms (CD1-3) that differ in their intracytoplasmic regions have been reported. Already two presumably pathogenic mutations (@VARIANT$ and @VARIANT$) have been found in exon 34 that is specific for CD1.",3125325,CDH23;11142,PCDH15;23401,p.M1853L;tmVar:p|SUB|M|1853|L;HGVS:p.M1853L;VariantGroup:286;CorrespondingGene:911,p.T1868del;tmVar:p|DEL|1868|T;HGVS:p.1868delT;VariantGroup:223;CorrespondingGene:65217,0
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother.",8152424,PROKR2;16368,DMXL2;41022,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 @VARIANT$ and @GENE$ @VARIANT$), 2F07 (@GENE$ c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A).",5887939,PRICKLE4;22752,CELSR1;7665,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/@GENE$ (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; p.Cys163del of KAL1) and NELF/TACR3 (c. 1160-13C>T of @GENE$ and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"@GENE$ functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in TIMP3 were identified (online supplementary table S2).",6161649,SCUBE2;36383,RASA1;2168,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in MAP4K4 (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in @GENE$ to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,SMAD1;21196,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [p.His736Arg]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,RASA1;2168,TIMP3;36322,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The expression of Drosophila Gcn5 (hereafter referred to as Gcn5 WT) with tub-GAL4 or another ubiquitous driver (daughterless (da)-@GENE$) led to a full rescue (S3B Fig and Fig 3C). By contrast, the expression of human KAT2A and @GENE$, either alone or in combination, did not restore the viability of the mutant (Fig 3C), suggesting that the human orthologs have evolved in structure and function in comparison to Gcn5. As the mutated amino acid in KAT2B, F307, is conserved in Drosophila Gcn5 (corresponding to Gcn5 F304), we re-expressed Gcn5 @VARIANT$ in the Gcn5E333st hemizygous background (Gcn5 F304S). As a negative control, we re-expressed a predicted potentially damaging KAT2B variant (@VARIANT$ corresponding to Gcn5 S478F) found in a homozygous state in a healthy individual from our in-house database.",5973622,GAL4;21239,KAT2B;20834,F304S;tmVar:p|SUB|F|304|S;HGVS:p.F304S;VariantGroup:6;CorrespondingGene:39431,S502F;tmVar:p|SUB|S|502|F;HGVS:p.S502F;VariantGroup:3;CorrespondingGene:8850;RS#:141445570;CA#:2284662,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"Since TTC26 is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between @GENE$ and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant @VARIANT$ and p.R197C @GENE$ proteins pulled down the Flag-tagged mutant p.A2282T and @VARIANT$ FLNB proteins, respectively (figure 2D, E).",7279190,FLNB;37480,TTC26;11786,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,p.R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,0
"The @VARIANT$ variant in GJB2 occurring in complex heterozygosity with a pathogenic GJB3 variant, @VARIANT$ from SH175-389, suggests a possible digenic etiology of SNHL involving two different gap junction proteins, Cx26 and Cx31. Large deletions in GJB6 (del [GJB6-D13S1830] and del [GJB6-D13S1854]) are frequently detected in a trans configuration with a monoallelic GJB2 mutation in certain populations. Based on these findings, it was previously hypothesized that variations in GJB2 and GJB6 in trans can cause SNHL through digenic inheritance. However, subsequent studies revealed that GJB6 deletions result in an allele-specific lack of GJB2 mRNA expression, contributing to SNHL in a manner not resulting from digenic inheritance. Nevertheless, a digenic etiology involving mutations in several gap junction genes has been proposed. Structurally, the gap junction is composed of two connexons (Cxs), which are formed by the oligomerization of six Cx subunits. Several Cx genes, including Cx26, @GENE$, Cx30, @GENE$, Cx32, Cx30.3, and Cx43, can induce SNHL.",4998745,Cx29;15399,Cx31;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing @GENE$/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [p.Cys531Tyr]) in SCUBE2 were identified (online supplementary table S2).",6161649,ENG;92,BMP;55955,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with @GENE$ p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,TARDBP;7221,VAPB;36163,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Moreover, the presence of other variants (@GENE$-@VARIANT$, KCNH2-p.K897T, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,1
"Four genes (including @GENE$, @GENE$, SCAP, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,AGXT2;12887,ZFHX3;21366,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"@GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (KCNQ1-p.R583H, KCNH2-@VARIANT$, and @GENE$-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Bioinformatic analysis predicted that KCNE1-@VARIANT$ was ""tolerated"" and KCNH2-C108Y was ""damaging"", whereas divergent results were obtained for KCNQ1-R583H and KCNH2-K897T, i.e., some programs considered these variants ""damaging"" and others as ""benign"" (Table 2). Moreover, the MAF of @GENE$-p.R583H was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of @GENE$-p.K897T and KCNE1-p.G38S were much larger (0.187 and 0.352, respectively). KCNH2-p.@VARIANT$ is not reported in the ExAC database.",5578023,KCNQ1;85014,KCNH2;201,G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Hence, @GENE$ mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (c.1165+1G>A) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (c.1070A>G, @VARIANT$) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (@VARIANT$), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"c.223 - 4C > A might affect the normal splicing of exons in the PROK2 gene, and the novel variant @VARIANT$ (p. Arg102Ser) was predicted to be harmful by multiple software programs. A few missense variants were detected in patients with a PROK2 gene, and most of the missense variants recorded in the ClinVar database were pathogenic. Three kinds of missense variants in the @GENE$ gene were found in eight patients. @VARIANT$ (p. Tyr113His) significantly decreased the receptor expression level and reduced intracellular calcium mobilization, resulting in protein instability and poor biological function. c.491G > A (p. Arg164Gln) destroyed the interaction between the IL2 domain and G-protein, inhibited Gq-protein signal activity, and weakened G protein-coupled receptors. The hot spot variant c.533G > C (p. Trp178Ser) was found in six patients and located in the transmembrane domain of the protein, which could significantly reduce the release of ionized calcium and the signal activity.                             The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the FGF/@GENE$ signalling pathway.",8796337,PROKR2;16368,FGFR1;69065,c.306G > C;tmVar:c|SUB|G|306|C;HGVS:c.306G>C;VariantGroup:27;CorrespondingGene:60675,c.337 T > C;tmVar:c|SUB|T|337|C;HGVS:c.337T>C;VariantGroup:0;CorrespondingGene:128674;RS#:202203360;CA#:9754374,0
"Nevertheless, the @VARIANT$ variant has also been considered a benign variant, due to its association with close to normal life expectancy (Tripathi et al., 2011).   Recently, Gifford et al., identified three missense variants in MKL2 (Gln670His), @GENE$ (Leu387Phe), and @GENE$ (@VARIANT$) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MYH7;68044,NKX2-5;1482;4824,p.Ile736Thr;tmVar:p|SUB|I|736|T;HGVS:p.I736T;VariantGroup:1;CorrespondingGene:4625;RS#:727503261(Expired),Ala119Ser;tmVar:p|SUB|A|119|S;HGVS:p.A119S;VariantGroup:0;CorrespondingGene:1482;RS#:137852684;CA#:120058,0
"a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and @GENE$ mutations. c Audiograms of the patient with mono-allelic @GENE$ @VARIANT$ and SLC26A4 @VARIANT$ mutations.",7067772,SLC26A4;20132,EPHA2;20929,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the @GENE$ gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,KCNE2;71688,LQT2;201,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"@GENE$, localized at chromosome 16q21, codify for a protein that belongs to the family of intracellular NLR (NOD-like receptors), able to recognize microbial components and to stimulate an inflammatory response through the activation of @GENE$. Moreover, three NOD2 mutations (rs2066844, @VARIANT$ and @VARIANT$) represent the main genetic factor causing susceptibility to CD.",3975370,NOD2;11156,NF-kappaB;2971,rs2066845;tmVar:rs2066845;VariantGroup:9;CorrespondingGene:64127;RS#:2066845,rs5743293;tmVar:rs5743293;VariantGroup:18;RS#:5743293,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,WNT10A;22525,EDA;1896,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"These phenomenon indicate that the mutated @GENE$-c.3035C>T (@VARIANT$) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. AGXT2-c.1103C>T (p.Ala338Val) variant impaired the catabolism of ADMA in EA. hy926 cell lines AGXT2-c.1103C>T (@VARIANT$) variant was introduced into EA. hy926 cell lines by CRISPR-Cas9 methodology. The conditioned medium was collected at the time point of 24h, 48h and 72h respectively after plant. Elisa analysis showed that the ADMA levels in group harboring a mutated @GENE$-c.1103C were significantly (n=4, P<0.05) higher than the wild-type group (Figure 5), indicating that the enzyme activity of the mutated AGXT2 coding protein was significantly impaired.",5725008,SCAP;8160,AGXT2;12887,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,p.Ala338Val;tmVar:p|SUB|A|338|V;HGVS:p.A338V;VariantGroup:5;CorrespondingGene:64902,0
"Allele frequency for @VARIANT$ within the population was calculated from exome sequencing of 2000 individuals and was found to be 0.1% (unpublished data from the Saudi Human Genome Project; www.saudigenomeprogram.org). Furthermore, 500 ethnically matched normal controls were genotyped for this change by re-sequencing of S100A3. Three of these individuals were heterozygous, but none was homozygous for rs138355706. Sequencing of the @GENE$ intronic and 5'-flanking sequences was performed in the affected patients and no other variants were identified (data not shown). The novel truncated variant in S100A13 was not found in our ""in-house"" Saudi exome data (unpublished data from the Saudi Human Genome Project), 1000 Genome and gnomAD databases. The c.229C>T (p.R77C) variant in S100A3 and @VARIANT$ (p.I80Gfs*13) mutation in @GENE$ also segregated fully with ILD in Families 1B and 2.",6637284,S100A3;2223,S100A13;7523,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,ALS2;23264,MATR3;7830,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and @GENE$ mutations at the same locus as that of N2 (Fig. 2B).",3842385,EDA;1896,WNT10A;22525,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Myopathy With SQSTM1 and @GENE$ Variants: Clinical and Pathological Features Objective The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Patients and methods Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in @GENE$ (@VARIANT$, p.Pro392Leu) and a heterozygous variant in TIA1 (@VARIANT$, p.Asn357Ser).",5868303,TIA1;20692,SQSTM1;31202,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic p.A194T variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, @GENE$ = microphthalmia-associated transcription factor.",4998745,GJB3;7338,MITF;4892,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,0
"However, none of these signs were evident from metabolic work of the patient with @GENE$ @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and @GENE$ @VARIANT$ variants remain unknown.",6072915,PHKA1;1981,NDUFS8;1867,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0
"                    By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). This 2-year-old female showed severe autosomal recessive SNHL with a mean hearing threshold of 87.5 dB HL.   Single Heterozygous GJB2 Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the p.T123N variant of GJB2. The pathogenic potential of the p.T123N variant is controversial. Three variants of USH2A (NM_007123), @VARIANT$, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and @GENE$ (ANK1) identified in SH 94-208).",4998745,USH2A;66151,Ankyrin 1;55427,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,R5143C;tmVar:p|SUB|R|5143|C;HGVS:p.R5143C;VariantGroup:6;CorrespondingGene:7399;RS#:145771342;CA#:182576,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in @GENE$. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (@VARIANT$).",3125325,USH2A;66151,CDH23;11142,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the COL6A3 (rs144651558), RYR1 (@VARIANT$), CAPN3 (@VARIANT$), and @GENE$ (rs144901249) genes. We hypothesized that the inheritance pattern could follow a digenic pattern of inheritance. Screening for these polymorphisms in an unaffected sister revealed the presence of all these same variants except for that in the CAPN3 gene. All variants were studied to determine their frequency and if they had been previously reported as mutations. They were also subjected to protein modeling programs, including SIFT, PolyPhen, and MutationTaster. This analysis indicated that the @GENE$ variant c.1663G>A (rs138172448), which results in a p.Val555Ile change, and the DES gene variant c.656C>T (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging.",6180278,DES;56469,CAPN3;52,rs143445685;tmVar:rs143445685;VariantGroup:1;CorrespondingGene:6261;RS#:143445685,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,0
"Results Family with inherited neutropaenia, monocytosis and hearing impairment associated with mutations in @GENE$ and MYO6. Pedigree, phenotypes and mutation status are indicated as per the key provided (a). Causative heterozygous mutations in GFI1 (p.N382S/@VARIANT$) and @GENE$ (@VARIANT$/c.3526A > C) were identified by whole exome sequencing performed on III-1 and IV-1.",7026993,GFI1;3854,MYO6;56417,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,p.I1176L;tmVar:p|SUB|I|1176|L;HGVS:p.I1176L;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: @VARIANT$, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,TOR2A;25260,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG @VARIANT$, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ p.G287S was found in combination with VAPB @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"The proband described by Forlani et al. was heterozygous for @GENE$ @VARIANT$ and @GENE$ R80Q. Both mutations are novel and whilst a different mutation, @VARIANT$, has been reported in HNF4A, further evidence to support the pathogenicity of E508K is lacking.",4090307,HNF1A;459,HNF4A;395,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,R80W;tmVar:p|SUB|R|80|W;HGVS:p.R80W;VariantGroup:2;CorrespondingGene:3172,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, @VARIANT$ (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the @GENE$ exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of NOD2 protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the @VARIANT$ substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, @VARIANT$ (p.Asn357Ser) and @GENE$, c.1175C > T (p.Pro392Leu). No other pathogenic or suspected pathogenic variants in genes associated with muscle diseases were identified in the proband of family 2 by expanded NGS panel studies or in the proband of family 1 by WES analysis.         We are aware of a prior study in which this SQSTM1 mutation may be part of a common founder haplotype including the following four loci: [Chr5: 179260153C/T, refSNP ID rs4935; Chr5: @VARIANT$, rs4797; Chr5: 179264731T/C, rs10277; Ch5: 179264915G/T, rs1065154 ].",5868303,TIA1;20692,SQSTM1;31202,c.1070A > G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,179260213G/A;tmVar:c|SUB|G|179260213|A;HGVS:c.179260213G>A;VariantGroup:0;CorrespondingGene:8878;RS#:4797;CA#:3600734,0
"RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"   Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the GCK gene and in exon 4 (c.872 C > G; @VARIANT$) of the HNF1A gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the GCK variant was present in the father and the HNF1A variant was present in the mother (Figure 1B). 4. Discussion Monogenic diabetes comprises a group of heterogeneous genetic disorders characterized by the early onset of diabetes, the absence of autoimmunity, and beta-cell dysfunction. Recognition of these forms of diabetes is crucial for reducing both the complications and the treatment costs associated with the disease, and to improve glycemic control with the most appropriate treatment and follow-up for patients. In particular, HNF1A/MODY patients are generally responsive to sulfonylureas, whereas, for GCK/MODY patients, no pharmacological treatment is recommended and diet and regular physical activity are sufficient to maintain good glycemic control. In this case report, we described an unusual molecular diagnosis performed by NGS analysis in a hyperglycemic child, which revealed two distinct genetic variants in the @GENE$ and @GENE$ genes.",8306687,GCK;55440,HNF1A;459,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,p.Pro291Arg;tmVar:p|SUB|P|291|R;HGVS:p.P291R;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,1
"Compared to WT (wild-type) proteins, we found that the ability of GFP-@GENE$ A115P and GFP-CYP1B1 @VARIANT$ to immunoprecipitate HA-TEK @VARIANT$ and HA-@GENE$ Q214P, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (c.46C>G; p.L16V) and @GENE$ (c.9921T>G).",3125325,USH1G;56113,USH2A;66151,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0
"Mutations in NRXN1 and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, p.Arg896Trp) and NRXN2 (@VARIANT$, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,c.3176G>A;tmVar:c|SUB|G|3176|A;HGVS:c.3176G>A;VariantGroup:2;CorrespondingGene:9379;RS#:777033569;CA#:6078001,0
"Six variants in PKD1 occurred de-novo, three of which were not previously described: @VARIANT$.(Asp1079Alafs*25), c.8860G>T p.(Glu2954*), and @VARIANT$. One de-novo and novel variant was also detected in PKD2: c.992G>A p.(Cys331Tyr). Types of 158 distinct possible pathogenic variants detected in @GENE$ and @GENE$ genes.",7224062,PKD1;250,PKD2;20104,c.3236del p;tmVar:c|DEL|3236|P;HGVS:c.3236delP;VariantGroup:47;CorrespondingGene:5310,c.9201+1G>A;tmVar:c|SUB|G|9201+1|A;HGVS:c.9201+1G>A;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and @VARIANT$, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the @VARIANT$ substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,c.1051A > G;tmVar:c|SUB|A|1051|G;HGVS:c.1051A>G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561;CA#:10006322,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, @VARIANT$, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"          In a second example, we identified a monoallelic change in SRD5A2 (c.G680A, p.Arg227Gln, @VARIANT$:G>A), in conjunction with the @VARIANT$ of @GENE$. Monoallelic inheritance of @GENE$, although uncommon, has been reported in a severely under-virilized individual with hypospadias and bilateral inguinal testes (Chavez, Ramos, Gomez, & Vilchis, 2014).",5765430,SF1;138518,SRD5A2;37292,rs9332964;tmVar:rs9332964;VariantGroup:0;CorrespondingGene:6716;RS#:9332964,single amino acid deletion at position 372;tmVar:|Allele|SINGLEAMINO|372;VariantGroup:20;CorrespondingGene:7536,0
"Compound heterozygous variants in DSCAML1, DSCAM and @GENE$ were retained. In two unrelated patients, AVM106 and AVM285, identical compound heterozygous variants were identified in DSCAML1: c.5783G>A (p.Arg1928His) and c.4574G>A (@VARIANT$), each inherited from heterozygous carrier parents (table 2). Both variants were reported in ExAC with an allele frequency <0.001, and they were predicted in silico to be highly deleterious (GERP++>4 and CADD>30 for both). In patient AVM226, we identified the compound heterozygous variants @VARIANT$ (p.Val1259Ile) and c.2966A>T (p.Gln989Leu) in @GENE$ (table 2).",6161649,PTPN13;7909,DSCAM;74393,p.Arg1525His;tmVar:p|SUB|R|1525|H;HGVS:p.R1525H;VariantGroup:5;CorrespondingGene:57453;RS#:1212415588,c.3775G>A;tmVar:c|SUB|G|3775|A;HGVS:c.3775G>A;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,0
"The DUSP6 gene [c.340G > T; @VARIANT$] was involved in all five disease-causing digenic combinations. Sanger sequencing showed that the @GENE$ variant [c.1759G > A; @VARIANT$] was only present in HH12 and absent in his asymptomatic mother (Figure 1). The variants located in the promoter region of @GENE$ were extracted, which revealed one common variant (c.-9 + 342A > G) in intron 1 with a MAF of 0.3 according to GnomAD.",8446458,SEMA7A;2678,PROKR2;16368,p.(Val114Leu);tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,p.(Glu587Lys);tmVar:p|SUB|E|587|K;HGVS:p.E587K;VariantGroup:7;CorrespondingGene:8482,0
"Two potential disease-causing mutations were identified: (d) ENAM: @VARIANT$/ p.Asn197Ilefs*81, which was previously reported to cause ADAI in multiple families (Hart, Hart, et al., 2003; Kang et al., 2009; Kida et al., 2002; Pavlic et al., 2007; Wright et al., 2011). (e) @GENE$ missense mutation @VARIANT$/p.Cys520Tyr. All recruited affected family members (II:2, II:4, III:1, III:2, III:3, and III:5) were heterozygous for both of these (@GENE$ and LAMA3) mutations.",6785452,LAMA3;18279,ENAM;9698,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,c.1559G>A;tmVar:c|SUB|G|1559|A;HGVS:c.1559G>A;VariantGroup:6;CorrespondingGene:3909,0
"C108Y Variants To investigate the functional consequences of KCNQ1-@VARIANT$ and @GENE$-p.C108Y, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells. KCNQ1-p.R583H mutant channels were investigated by analyzing ionic currents from cells expressing the wild-type (WT) channel (KCNQ1-WT) or KCNQ1-p.R583H and from cells co-expressing the KCNQ1 and KCNE1 subunits (@GENE$-WT+KCNE1 or KCNQ1-p.R583H+KCNE1), which reconstitute the slow delayed rectifier potassium current (IKs). The functional consequence of KCNH2-p.C108Y was investigated by analyzing the ionic currents from cells expressing KCNH2-WT or KCNH2-@VARIANT$ and from cells co-expressing both alleles.",5578023,KCNH2;201,KCNQ1;85014,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"All but 1 patient had a @GENE$ mutation in association with mutation(s) in different genes. A total of 2 novel variants, p.S309P and @VARIANT$, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 @GENE$ variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The TSHR variant p.R450H was a recurrent inactivating mutation and p.C176R and @VARIANT$ were novel.",7248516,TPO;461,TSHR;315,p.S571R;tmVar:p|SUB|S|571|R;HGVS:p.S571R;VariantGroup:26;CorrespondingGene:79048;RS#:765990605,p.K618;tmVar:p|Allele|K|618;VariantGroup:4;CorrespondingGene:7253,0
"The detected R572W variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected.",6707335,CCNF;1335,ALS2;23264,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"The @VARIANT$ variant in @GENE$ occurring in complex heterozygosity with a pathogenic GJB3 variant, @VARIANT$ from SH175-389, suggests a possible digenic etiology of SNHL involving two different gap junction proteins, Cx26 and @GENE$. Large deletions in GJB6 (del [GJB6-D13S1830] and del [GJB6-D13S1854]) are frequently detected in a trans configuration with a monoallelic GJB2 mutation in certain populations.",4998745,GJB2;2975,Cx31;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"    In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (p.Ser334Thr) were identified in PTPN13 (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, @VARIANT$ (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,ENG;92,MAP4K4;7442,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"All but 1 patient had a @GENE$ mutation in association with mutation(s) in different genes. A total of 2 novel variants, @VARIANT$ and p.S571R, were located in a myeloperoxidase-like domain, the catalytic site of the enzyme (Fig. S3B). A total of 4 TSHR variants were found in 2 patients and were compound heterozygotes for 2 different TSHR mutations. The @GENE$ variant p.R450H was a recurrent inactivating mutation and p.C176R and p.K618 were novel. p.C176R is located in the leucine-rich repeat region of the extracellular domain and responsible for high-affinity hormone binding and @VARIANT$ and p.K618* are located in the cytoplasmic loops (Fig. S3C).",7248516,TPO;461,TSHR;315,p.S309P;tmVar:p|SUB|S|309|P;HGVS:p.S309P;VariantGroup:13;CorrespondingGene:2304;RS#:1162674885,p.R528S;tmVar:p|SUB|R|528|S;HGVS:p.R528S;VariantGroup:25;CorrespondingGene:7253;RS#:765367813,0
"A concomitant gain-of-function variant in the sodium channel gene @GENE$ (@VARIANT$) was found to rescue the phenotype of the female CACNA1C-@VARIANT$ mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the @GENE$-Q1916R mutation led to a decreasing L-type calcium current and the protein expression defect.",5426766,SCN5A;22738,CACNA1C;55484,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"This de novo variant may modify the effect of the truncating variant in @GENE$ by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (@VARIANT$ [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,ENG;92,SCUBE2;36383,c.1592G>A;tmVar:c|SUB|G|1592|A;HGVS:c.1592G>A;VariantGroup:5;CorrespondingGene:1956;RS#:1212415588,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"For example, two variants in proband P15, @VARIANT$ in @GENE$ and p. Tyr503His in DDB1 and CUL4 associated factor 17 (@GENE$), were inherited from unaffected father, while DMXL2 @VARIANT$ variant was inherited from unaffected mother.",8152424,PROKR2;16368,DCAF17;65979,p. Ala103Val;tmVar:p|SUB|A|103|V;HGVS:p.A103V;VariantGroup:20;CorrespondingGene:128674;RS#:775634673;CA#:9754381,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (LQT2) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,KCNE2;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance.",6707335,CCNF;1335,ALS2;23264,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and @VARIANT$ (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,I148T;tmVar:p|SUB|I|148|T;HGVS:p.I148T;VariantGroup:5;CorrespondingGene:7010;RS#:35969327;CA#:5015918,0
"In subject 10035, a deleterious variant within the DYT21 (Chr2) locus was identified in @GENE$ (OMIM 612981; @VARIANT$, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in @GENE$ (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and ARHGEF19 (OMIM 612496; rs144638812, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus.",6081235,IMP4;68891,UBR4;10804,rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,1
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and LQT6.",6610752,KCNE2;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,1
"Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),0
"Mutations in @GENE$ and @GENE$ in a patient with early-onset epileptic encephalopathy and respiratory depression Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, @VARIANT$) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In patient AVM226, we identified the compound heterozygous variants @VARIANT$ (p.Val1259Ile) and c.2966A>T (@VARIANT$) in DSCAM (table 2). @GENE$ and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.",6161649,DSCAML1;79549,DSCAM;74393,c.3775G>A;tmVar:c|SUB|G|3775|A;HGVS:c.3775G>A;VariantGroup:5;CorrespondingGene:1826;RS#:1212415588,p.Gln989Leu;tmVar:p|SUB|Q|989|L;HGVS:p.Q989L;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The functional impact of the second @GENE$ amino acid substitution, @VARIANT$, could not be functionally evaluated due to DNA cloning difficulties. In fact, the two @GENE$ amino acid changes were found to be hypomorphic whereas the PITX2 amino acid substitution (@VARIANT$) behaved experimentally as a hypermorphic variant.",6338360,PITX2;55454,FOXC2;21091,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"                                 CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, @GENE$ @VARIANT$ and @GENE$ p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"The @VARIANT$ (p.R77C) variant in S100A3 and @VARIANT$ (p.I80Gfs*13) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.             Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, @GENE$ and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
"Interestingly, four of these @GENE$ mutations (p.E103D, p.I148T, p.Q214P, and @VARIANT$) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (@VARIANT$, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or @GENE$ alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,TEK;397,CYP1B1;68035,p.G743A;tmVar:p|SUB|G|743|A;HGVS:p.G743A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of GJB2 and a monoallelic @VARIANT$ variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = @GENE$, MITF = microphthalmia-associated transcription factor.",4998745,GJB3;7338,gap junction protein beta 6;4936,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In patient AVM558, the de novo heterozygous missense variant @VARIANT$ (p.Arg565Gln) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3). Loss of MAP4K4 leads to impaired angiogenesis in vitro and in vivo.  In patient AVM206, the de novo heterozygous missense variant c.2075A>G (@VARIANT$) was identified in @GENE$ (table 1), which encodes N-cadherin, an integral mediator of cell-cell interactions.",6161649,MAP4K4;7442,CDH2;20424,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,p.Asn692Ser;tmVar:p|SUB|N|692|S;HGVS:p.N692S;VariantGroup:10;CorrespondingGene:83394;RS#:762863730,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation @VARIANT$ and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
R583H variant was previously reported to be associated with LQTS; KCNH2-@VARIANT$ is a novel variant; and @GENE$-p.K897T and @GENE$-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels.,5578023,KCNH2;201,KCNE1;3753,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The @VARIANT$ (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of @VARIANT$. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),Gly at residue 213 to Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (@VARIANT$). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants c.5792A>G; @VARIANT$), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,FZD;8321;8323,FAT4;14377,c.1892C>T;tmVar:c|SUB|C|1892|T;HGVS:c.1892C>T;VariantGroup:35;CorrespondingGene:1952;RS#:41279706;CA#:986652,c.10384A>G;tmVar:c|SUB|A|10384|G;HGVS:c.10384A>G;VariantGroup:2;CorrespondingGene:4824;RS#:373263457;CA#:4677776,0
"The c.1592G>A (@VARIANT$) @GENE$ variant could induce BAVMs via a gain-of-function mechanism, though confirmation will require further functional studies. In patient AVM558, the de novo heterozygous missense variant @VARIANT$ (p.Arg565Gln) was identified in @GENE$ (table 1), which encodes a kinase responsible for phosphorylation of residue T312 within SMAD1, blocking SMAD1 activity in BMP/TGF-beta signalling (figure 3).",6161649,SCUBE2;36383,MAP4K4;7442,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,c.1694G>A;tmVar:c|SUB|G|1694|A;HGVS:c.1694G>A;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"M1, @GENE$: @VARIANT$. M2, CYP1B1: p.(E387K). M3, CYP1B1: p.(E173*). M4, @GENE$: p.(P179T). M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(A179fs*18);tmVar:p|FS|A|179||18;HGVS:p.A179fsX18;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, @GENE$ @VARIANT$, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,ANG;74385,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, p. A85P, p.L86F, @VARIANT$, p.R127L, p.G149D, and @VARIANT$, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p.F112S;tmVar:p|SUB|F|112|S;HGVS:p.F112S;VariantGroup:9;CorrespondingGene:2296;RS#:104893951;CA#:119636,p.R170W;tmVar:p|SUB|R|170|W;HGVS:p.R170W;VariantGroup:59;CorrespondingGene:1805,0
"The @VARIANT$ (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and @GENE$ p.R408C with @GENE$ @VARIANT$ and SETX @VARIANT$).,4293318,TAF15;131088,SETX;41003,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the arginine residue to cysteine at position 77 of the S100A3 protein (@VARIANT$; p.R77C) and d) the @VARIANT$ (p.I80Gfs*13) in @GENE$. Mutation name is based on the full-length @GENE$ (NM_002960) and S100A13 (NM_001024210) transcripts.",6637284,S100A13;7523,S100A3;2223,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,c.238-241delATTG;tmVar:c|DEL|238_241|ATTG;HGVS:c.238_241delATTG;VariantGroup:13;CorrespondingGene:6284,0
Further segregation analyses of the two variants (p.R143W and p.D771N) among the six family members of SH60 as well as clinical evaluations including audiograms excluded both @VARIANT$ of @GENE$ and @VARIANT$ of @GENE$ as a molecular etiology of SH60-136.,4998745,GJB2;2975,WFS1;4380,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"@GENE$, localized at chromosome 16q21, codify for a protein that belongs to the family of intracellular NLR (NOD-like receptors), able to recognize microbial components and to stimulate an inflammatory response through the activation of @GENE$. Moreover, three NOD2 mutations (@VARIANT$, rs2066845 and @VARIANT$) represent the main genetic factor causing susceptibility to CD.",3975370,NOD2;11156,NF-kappaB;2971,rs2066844;tmVar:rs2066844;VariantGroup:8;CorrespondingGene:64127;RS#:2066844,rs5743293;tmVar:rs5743293;VariantGroup:18;RS#:5743293,0
"However, the KS patient carrying the @VARIANT$ mutation in @GENE$ suffers from a severe sleep disorder and marked obesity, which might be related to the known circadian function of prokineticin-2 and its potential roles in sleep-wake regulation and ingestive behavior. In human monogenic disorders, genuine dominance, where heterozygotes and homozygotes have the same phenotype, is unusual. In particular, most dominant developmental diseases are far more severe in the homozygous state. Therefore, the finding of both heterozygous and homozygous (or compound heterozygous) KS patients for a given mutation in @GENE$ (e.g., p.R85H or @VARIANT$, see Table 1) is quite remarkable and raises the question of a possible digenic mode of inheritance in heterozygous patients.",161730,PROK2;9268,PROKR2;16368,p.R73C;tmVar:p|SUB|R|73|C;HGVS:p.R73C;VariantGroup:1;CorrespondingGene:60675;RS#:121434272;CA#:252842,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,0
"For example, two variants in proband P15, p. Ala103Val in @GENE$ and @VARIANT$ in @GENE$ (DCAF17), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$).",8152424,PROKR2;16368,DDB1 and CUL4 associated factor 17;80067;1642,p. Tyr503His;tmVar:p|SUB|Y|503|H;HGVS:p.Y503H;VariantGroup:12;CorrespondingGene:10908;RS#:184906487,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"We identified variants in two genes in family A. The first variant is @VARIANT$ in @GENE$, a well-documented missense variant that has been classified as pathogenic in its association with HCM and previously reported in the Atlas of Cardiac Genetic Variation and ClinVar. The second variant is a novel, missense variant in @GENE$ (@VARIANT$), not reported in control databases including gnomAD, GME Variome, and dbSNP.",6359299,MYH7;68044,LAMA4;37604,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,1
"Moreover, the MAF of @GENE$-p.R583H was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and @GENE$-@VARIANT$ were much larger (0.187 and 0.352, respectively). KCNH2-p.@VARIANT$ is not reported in the ExAC database.",5578023,KCNQ1;85014,KCNE1;3753,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"CVID, common variable immunodeficiency disorder; SLE, systemic lupus erythematosus; sIgAD, selective IgA deficiency; T1D, Type 1 Diabetes, sHGUS, symptomatic hypogammglobulinaemia of uncertain significance; WT, wild-type. (b) Electropherograms showing the @VARIANT$ mutation of TCF3 and @VARIANT$ (c.310T>C) mutation of @GENE$ gene in the proband II.2. The proband's son (III.1) has inherited the @GENE$ T168fsX191 mutation, but not the TNFRSF13B/TACI C104R mutation.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Neither the @VARIANT$ nor the @VARIANT$ variant has been reported as a mutation of a compound heterozygote in patients diagnosed with a myopathy secondary to mutations in either the DES or CAPN genes. Discussion The patient's history, clinical examination, EMG testing, muscle biopsy results, and the lack of response to any therapy suggest that he does not have an inflammatory myopathy but rather a genetic disorder. Mutations in @GENE$ and @GENE$ genes result in LGMD inherited in an autosomal recessive pattern.",6180278,CAPN3;52,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"The @GENE$ missense variant @VARIANT$ was heterozygous in case P05. CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant p. Arg1299Cys was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, tachykinin receptor 3 (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)p. Gln91Arg, and @GENE$ @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,CCDC88C;18903,FGFR1;69065,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,1
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, @VARIANT$, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.E229K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, @VARIANT$, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and c.5749G>T in @GENE$, c.238_239dupC in USH1C, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.1996C>T;tmVar:c|SUB|C|1996|T;HGVS:c.1996C>T;VariantGroup:4;CorrespondingGene:4647;RS#:121965085;CA#:277967,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"Finally, for Case 7 and her father, a previously reported ZFPM2/FOG2 (@VARIANT$; p.Met544Ile) pathogenic missense alteration was identified. No additional variants in other genes associated with testicular development and DSD were identified by our panel in Cases 3, 5 and 6. We were not able to further analyze Case 4 because of a lack of sample availability. 2.3. Transcription Activity and Protein Expression Testing of Novel NR5A1 Variants To study the impact of the three novel missense variants of NR5A1 on transactivation activity of regulated genes, HEK293 cells were co-transfected with WT or mutant NR5A1 expression vectors and three different promoter reporter constructs essential for steroid and sex hormone biosynthesis. All three novel @GENE$ variants had significantly reduced activity on the CYP17A1 reporter compared to WT (Figure 2A). These results were confirmed for the His24Leu and @VARIANT$ variants when using the reporters for CYP11A1 and HSD17B3 (Figure 2B,C). In contrast, variant Cys301Tyr did not change the reporter activities of @GENE$ and HSD17B3 (Figure 2B,C).",7696449,NR5A1;3638,CYP11A1;37347,c.1632G>A;tmVar:c|SUB|G|1632|A;HGVS:c.1632G>A;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,Cys30Ser;tmVar:p|SUB|C|30|S;HGVS:p.C30S;VariantGroup:5;CorrespondingGene:6662;RS#:1003847603;CA#:293780979,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes. (A) The EDA mutation c.769G>C and WNT10A mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Below symbols are indicated genotypes for @GENE$ and @GENE$, age at diagnosis and number or surgical operations per eye, respectively. M1, CYP1B1: p.(A179fs*18). M2, CYP1B1: p.(E387K). M3, CYP1B1: p.(E173*). M4, PITX2: @VARIANT$. M5, PITX2: @VARIANT$. Arrows show the index cases.",6338360,CYP1B1;68035,PITX2;55454,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the KCNH2 gene (@GENE$) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT5;71688,LQT2;201,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/Cx31 connexons.",2737700,GJB3;7338,Cx26;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, @VARIANT$) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,TOR2A;25260,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,p.Arg656Cys;tmVar:p|SUB|R|656|C;HGVS:p.R656C;VariantGroup:21;CorrespondingGene:489;RS#:140404080;CA#:8297011,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (p.Arg1033ValfsX26) mutation of the KCNH2 gene (@GENE$) and a heterozygous @VARIANT$ (p.Ile57Thr) unclassified variant (UV) of the @GENE$ gene (LQT6).",6610752,LQT2;201,KCNE2;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,1
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous @VARIANT$ (@VARIANT$) mutation of the @GENE$ gene (LQT2) and a heterozygous c.170T > C (p.Ile57Thr) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the @GENE$ gene is likely a pathogenic mutation, what results in the digenic inheritance of LQT2 and LQT6.",6610752,KCNH2;201,KCNE2;71688,c.3092_3096dup;tmVar:c|DUP|3092_3096||;HGVS:c.3092_3096dup;VariantGroup:2;CorrespondingGene:9992,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in @GENE$ (@VARIANT$;p.R85C) inherited from an unaffected mother, and a WDR11 (c.1306A>G;@VARIANT$) mutation inherited from an unaffected father. Mutant @GENE$ loses its capacity to bind to its functional partner, EMX1, and to localize to the nucleus.",5505202,PROKR2;16368,WDR11;41229,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SNAI2;31127,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ @VARIANT$ and PRICKLE4 c.730C>G), 2F07 (CELSR1 c.8807C>T and @GENE$ @VARIANT$), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A).",5887939,CELSR1;7665,DVL3;20928,c.6362G>A;tmVar:c|SUB|G|6362|A;HGVS:c.6362G>A;VariantGroup:33;CorrespondingGene:9620;RS#:765148329;CA#:10293808,c.1622C>T;tmVar:c|SUB|C|1622|T;HGVS:c.1622C>T;VariantGroup:5;CorrespondingGene:1857;RS#:1311053970,0
"We identified a novel compound heterozygous variant in @GENE$ @VARIANT$ (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of BBS2 (@VARIANT$; p.(Asn354Lys)); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(Cys412Phe).",6567512,BBS1;11641,BBS7;12395,c.1285dup;tmVar:c|DUP|1285||;HGVS:c.1285dup;VariantGroup:20;CorrespondingGene:582,c.1062C > G;tmVar:c|SUB|C|1062|G;HGVS:c.1062C>G;VariantGroup:22;CorrespondingGene:583,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, @VARIANT$) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the @GENE$ and @GENE$ proteins lead us to hypothesize that digenic variants in NRXN1 and NRXN2 contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"25  The RYR3 (NM_001036: @VARIANT$, p.Asn2604Lys) and @GENE$ (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: c.55G > T, @VARIANT$) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, TRIP6 variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25  The contribution of the genetic variants, other than MSH6 and @GENE$, to cancer risk cannot be completely excluded.",7689793,EBNA1BP2;4969,MUTYH;8156,c.7812C > G;tmVar:c|SUB|C|7812|G;HGVS:c.7812C>G;VariantGroup:10;CorrespondingGene:6263;RS#:41279214;CA#:7459988,p.Ala19Ser;tmVar:p|SUB|A|19|S;HGVS:p.A19S;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 @VARIANT$, PTK7 p.P642R, SCRIB @VARIANT$, @GENE$ p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish. The four other variants (@GENE$ p.Q2924H, CELSR1 p.R1057C and SCRIB p.R1044Q) involved less conserved nucleotides (Supplemental material, Fig. S2).",5966321,SCRIB;44228,CELSR1;7665,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"These results suggest an important role of @GENE$ as an inducer of EphA2 endocytosis with the transmembrane binding partner, pendrin, while its effect is weaker than that of ephrin-A1.           Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/ephrin-B2 regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, L445W, Q446R, @VARIANT$ were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin L117F, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated @GENE$ triggered by ephrin-B2 stimulation.",7067772,ephrin-B2;3019,pendrin;20132,G672E;tmVar:p|SUB|G|672|E;HGVS:p.G672E;VariantGroup:2;CorrespondingGene:5172;RS#:111033309;CA#:261423,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,SNAI3;8500,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We did not find a mutation in @GENE$ in any of the individuals carrying a mutation in PROKR2 or PROK2, either. However, one of the patients heterozygous for the @VARIANT$ mutation in PROKR2 (sporadic case) also carried a previously undescribed missense mutation, @VARIANT$, in @GENE$ exon 8 (Figure S3), which was not detected in 500 alleles from control individuals.",161730,FGFR1;69065,KAL1;55445,p.L173R;tmVar:p|SUB|L|173|R;HGVS:p.L173R;VariantGroup:2;CorrespondingGene:128674;RS#:74315416;CA#:259599,p.S396L;tmVar:p|SUB|S|396|L;HGVS:p.S396L;VariantGroup:3;CorrespondingGene:3730;RS#:137852517;CA#:254972,0
"An HA tag was added in frame, before the stop codon, to the C terminus of @GENE$ and KAT2B. The ADD3 @VARIANT$ and @GENE$ @VARIANT$ mutations found in affected individuals were introduced with the QuickChange site-directed mutagenesis kit (Stratagene) according to the manufacturer's protocol.",5973622,ADD3;40893,KAT2B;20834,E659Q;tmVar:p|SUB|E|659|Q;HGVS:p.E659Q;VariantGroup:4;CorrespondingGene:120;RS#:753083630;CA#:5686787,F307S;tmVar:p|SUB|F|307|S;HGVS:p.F307S;VariantGroup:1;CorrespondingGene:8850,0
"However, it was hard to determine whether the coexisting interactions of @GENE$ p.307_308del and @GENE$ p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and SCN5A p.R1865H, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction. KCNH2 p.307_308del may affect the function of Kv11.1 channel in cardiomyocytes by inducing a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized. SCN5A @VARIANT$ reduced the instability index of Nav1.5 protein and sodium current. All of these were closely related to young early-onset LQTS and sinoatrial node dysfunction.   LIMITATIONS Our study was performed only in the statistical field on KCNH2 @VARIANT$ and SCN5A p.R1865H by WES and predisposing genes analyses.",8739608,KCNH2;201,SCN5A;22738,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous @VARIANT$ (c.511C>T) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,p.Arg171Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and @GENE$ mutations.",5953556,CYP1B1;68035,TEK;397,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"In subject 10035, a deleterious variant within the @GENE$ (Chr2) locus was identified in IMP4 (OMIM 612981; @VARIANT$, CADD_phred = 29.3, MetaLR = 0.83, REVEL = 0.606, gnomAD = 5.1E-04, Data S1), and deleterious variants in UBR4 (OMIM 609890; @VARIANT$, CADD_phred = 23.3, REVEL = 0.188, MetaLR = 0.46, MutationTaster2 = 0.81 [disease causing], gnomAD = 5.1E-04, Data S1), and ARHGEF19 (OMIM 612496; rs144638812, CADD_phred = 22.7, MetaLR = 0.64, REVEL = 0.11, MutationTaster2 = 0.55 [disease causing], gnomAD = 2.3E-04, Data S1) were identified in the DYT13 (Chr1) locus. To date, IMP4 and @GENE$ have not been linked to a medical disorder.",6081235,DYT21;100885773,ARHGEF19;17710,rs146322628;tmVar:rs146322628;VariantGroup:19;CorrespondingGene:92856;RS#:146322628,rs748114415;tmVar:rs748114415;VariantGroup:27;CorrespondingGene:23352;RS#:748114415,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"None of the variants in genes previously associated with HI segregated with the HI phenotype with the exception of the PCDH15 [GRCh37/hg19; chr10:@VARIANT$; NM_033056: c.3101G > A; p.(Arg1034His)] and @GENE$ [GRCh37/hg19; chr17:72915838C > T; NM_173477:@VARIANT$; p.(Asp365Asn)] variants which displayed digenic inheritance (Fig. 1a).                   The @GENE$ variant [NM_033056: c.3101G > A; p.(Arg1034His)] has a CADD score of 23.9, is predicted damaging according to MutationTaster, and is conserved amongst species (GERP++ RS 4.53 and PhyloP20way 0.892).",6053831,USH1G;56113,PCDH15;23401,55719513C > T;tmVar:g|SUB|C|55719513|T;HGVS:g.55719513C>T;VariantGroup:5;CorrespondingGene:65217,c.1093G > A;tmVar:c|SUB|G|1093|A;HGVS:c.1093G>A;VariantGroup:1;CorrespondingGene:124590;RS#:538983393;CA#:8753931,0
"Our data indicate that a normal level of @GENE$ is required to prevent secretion of abnormally folded pro-COL1A1. These data also indicate that an alternate pathway is used for quality control of pro-COL1A1 when MAN1B1 alpha-mannosidase activity is reduced. DISCUSSION In this study, we describe identification and characterization of abnormalities in patients with homozygous mutations in two genes, a novel mutation in SEC23A, @VARIANT$ and a previously identified mutation in MAN1B1, @VARIANT$. The affected patients presented with moderate global developmental delay, tall stature, obesity, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability, and flat feet. We found that mutations in the two genes segregated in the family and that the unaffected parents were healthy and carried heterozygous mutations in both @GENE$ and MAN1B1, consistent with an autosomal-recessive mode of inheritance.",4853519,MAN1B1;5230,SEC23A;4642,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"However, SCN5A @VARIANT$ showed no significant influence on the RNA structure (Figure 4c,d). The MFE of @GENE$ p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.           RNA secondary structural prediction. (a, b) Compared with wild-type @GENE$, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 p.307_308del increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A p.R1865H mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 @VARIANT$ showed a decreasing trend in molecular weight and increasing instability.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ @VARIANT$, pendrin S166N, and pendrin @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,1
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of @GENE$, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,NELF;10648,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB6;4936,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a). The c.1787A>G (@VARIANT$) mutation of SLC20A2 has been reported in a 66-year-old patient with sporadic primary familial brain calcification who was also clinically asymptomatic (Guo et al., 2019).",8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"Of the 3 novel variants in DUOX2, p.T803fs was a frameshift mutation and had a potential deleterious effect on protein function and @VARIANT$ and @VARIANT$ were missense mutations located in the peroxidase-like domain (Fig. S3A).  A total of 9 variants in TG were identified in 8 CH patients (8/43, 18.6%), 2 of which had >=2 TG variants. Apart from carrying TG mutation(s), 6 cases also had mutation(s) in genes associated with DH (@GENE$, DUOX2, @GENE$ and TPO).",7248516,SLC26A4;20132,DUOXA2;57037,p.D137E;tmVar:p|SUB|D|137|E;HGVS:p.D137E;VariantGroup:59;CorrespondingGene:50506,p.E389K;tmVar:p|SUB|E|389|K;HGVS:p.E389K;VariantGroup:1;CorrespondingGene:7253;RS#:377424991,0
"Interestingly, four of these TEK mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene @GENE$ (p.A115P, p.E229K, and @VARIANT$) in five families. The parents of these probands harbored either of the heterozygous @GENE$ or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance.",5953556,CYP1B1;68035,TEK;397,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0
"(a) Digenic inheritance of TNFRSF13B (c.310T>C, @VARIANT$ TACI) and TCF3 (T168fx191) mutations in a three-generation New Zealand family. Whole-exome sequencing was performed on II.2, III.1 and III.2 (indicated by *). The proband (II.2) is indicated by an arrow. Circles, female; squares, male; gray, @GENE$/TACI C104R mutation; blue @GENE$ @VARIANT$ mutation (as indicated).",5671988,TNFRSF13B;49320,TCF3;2408,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
"   Missense variants in the NEFH gene were detected in four patients: the @VARIANT$ variant in two cases and the R148P and P505L variants in single cases. NEFH encodes the heavy neurofilament protein, and its variants have been associated with neuronal damage in ALS. The T338I and R148P variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,0
"          Considering the clinical association of the PXE-like cutaneous features with coagulation disorder in this family, we also sequenced the @GENE$ and @GENE$ genes. The results demonstrated the presence of two missense mutations in GGCX. First, a single-base transition mutation (c.791G A) resulting in substitution of a valine by methionine at position 255 (p.V255M) of the gamma-glutamyl carboxylase enzyme was detected (Fig. 3b). This mutation was not present in 100 control alleles by restriction enzyme digestion and/or by direct nucleotide sequencing (Fig. 3c). Secondly, a single nucleotide substitution (@VARIANT$ T) resulting in substitution of a serine by phenylalanine in position 300 (@VARIANT$) was detected (Fig. 3d).",2900916,GGCX;639,VKORC1;11416,c.927C;tmVar:c|Allele|C|927;VariantGroup:3;CorrespondingGene:368;RS#:528603039,p.S300F;tmVar:p|SUB|S|300|F;HGVS:p.S300F;VariantGroup:16;CorrespondingGene:2677;RS#:121909684;CA#:214948,0
"    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in MYOD1 and a heterozygous missense variant c.190G>A(@VARIANT$) in MEOX1 (Table 2). CSS170323 presented with L2 hemivertebra and fused ribs (the right 11th rib and 12th rib). During mesoderm development, the expression of @GENE$ is increased by @GENE$ (Gianakopoulos et al., 2011), suggesting that these two variant potentially result in the cumulative perturbation of TBX6-mediated pathway.",7549550,MEOX1;3326,MYOD1;7857,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,1
"Under the assumption of an autosomal recessive inheritance pattern, two variants were identified in @GENE$ (@VARIANT$, p.(Lys111Glnfs*27) and c.7117C>T, p.(Gln2373*)) (Table 1, S3 Fig.). Segregation analysis showed that they were both present on the maternal allele (Figs. 1C-D). By analyzing for the presence of variants in genes implicated in intellectual disability, hearing impairment and inherited retinal disease, a heterozygous stop mutation in @GENE$ (@VARIANT$, p.(Ser512*)), a gene previously shown to be involved in autosomal recessive RP.",5967407,RP1L1;105870,C2orf71;19792,c.326_327insT;tmVar:c|INS|326_327|T;HGVS:c.326_327insT;VariantGroup:0;CorrespondingGene:94137;RS#:771427543;CA#:4625758,c.1535C>A;tmVar:c|SUB|C|1535|A;HGVS:c.1535C>A;VariantGroup:1;CorrespondingGene:388939;RS#:1293811678,1
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and @GENE$ proteins to associate with wild-type CYP1B1 and TEK, respectively. As shown in Supplementary Fig. 3a, the mutant HA-TEK proteins E103D and I148T exhibited diminished interaction with wild-type GFP-CYP1B1. On the other hand, mutant GFP-CYP1B1 A115P and R368H showed perturbed interaction with HA-@GENE$. The residues E103, @VARIANT$, and Q214 lie in the N-terminal extracellular domain of TEK (Fig. 1d).",5953556,CYP1B1;68035,TEK;397,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,I148;tmVar:p|Allele|I|148;VariantGroup:5;CorrespondingGene:7010;RS#:35969327,0
"In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in @GENE$. To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,GJB6;4936,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In two unrelated patients, AVM106 and AVM285, identical compound heterozygous variants were identified in DSCAML1: c.5783G>A (@VARIANT$) and c.4574G>A (p.Arg1525His), each inherited from heterozygous carrier parents (table 2). Both variants were reported in ExAC with an allele frequency <0.001, and they were predicted in silico to be highly deleterious (GERP++>4 and CADD>30 for both). In patient AVM226, we identified the compound heterozygous variants c.3775G>A (p.Val1259Ile) and c.2966A>T (@VARIANT$) in DSCAM (table 2). DSCAML1 and @GENE$ have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2).",6161649,DSCAM;74393,PTPN13;7909,p.Arg1928His;tmVar:p|SUB|R|1928|H;HGVS:p.R1928H;VariantGroup:5;CorrespondingGene:57453;RS#:1212415588,p.Gln989Leu;tmVar:p|SUB|Q|989|L;HGVS:p.Q989L;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,0
"(D) SH175-389 harbored a monoallelic @VARIANT$ variant of @GENE$ and a monoallelic @VARIANT$ variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,KAL1;55445,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Among the six variants (Table 2), two are missense variants in the RNA Binding Motif Protein 43 (@GENE$) gene (@VARIANT$) and the @GENE$ (DPT) gene (@VARIANT$).",5611365,RBM43;12715,dermatopontin;1458,p.V34L;tmVar:p|SUB|V|34|L;HGVS:p.V34L;VariantGroup:31;CorrespondingGene:375287;RS#:147060862;CA#:1902988,p.Y149C;tmVar:p|SUB|Y|149|C;HGVS:p.Y149C;VariantGroup:15;CorrespondingGene:1805;RS#:777651623;CA#:1231264,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to SCRIB and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,CELSR1;7665,PTK7;43672,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, @GENE$ = gap junction protein beta 2, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (@VARIANT$) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in @GENE$ (g.27546T>A, c.379T>A, @VARIANT$; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A).",8621929,LRP6;1747,WNT10A;22525,p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
He is a carrier of @GENE$ (MIM 606463; GenBank: NM_001005741.2; rs7673715) c.1226A>G; @VARIANT$ and @GENE$ (MIM 600509; NM_000352.4; @VARIANT$) c.3989-9G>A mutations.,5505202,GBA;68040,ABCC8;68048,p.N409S;tmVar:p|SUB|N|409|S;HGVS:p.N409S;VariantGroup:7;CorrespondingGene:2629;RS#:76763715;CA#:116767,rs151344623;tmVar:rs151344623;VariantGroup:4;CorrespondingGene:6833;RS#:151344623,1
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (@VARIANT$ and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 @VARIANT$, CELSR1 p.R769W, @GENE$ @VARIANT$, @GENE$ p.P642R, SCRIB p.G1108E, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,DVL3;20928,PTK7;43672,p.G1122S;tmVar:p|SUB|G|1122|S;HGVS:p.G1122S;VariantGroup:0;CorrespondingGene:9620;RS#:200363699;CA#:10295026,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of KAL1) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of @GENE$).,3888818,NELF;10648,TACR3;824,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, @GENE$: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and SLC26A4: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"This genetic synergism is also supported by the potential digenic inheritance of @GENE$ and @GENE$ mutations in Family 4. The proband, who had LRP6 p.(@VARIANT$), p.(Ser127Thr), and WNT10A p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,1
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, @VARIANT$, c.494C>T, c.3719G>A and c.5749G>T in MYO7A, c.238_239dupC in @GENE$, and @VARIANT$ and c.10712C>T in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,USH1C;77476,USH2A;66151,c.1556G>A;tmVar:c|SUB|G|1556|A;HGVS:c.1556G>A;VariantGroup:9;CorrespondingGene:4647;RS#:111033206;CA#:278629,c.2299delG;tmVar:c|DEL|2299|G;HGVS:c.2299delG;VariantGroup:190;CorrespondingGene:7399;RS#:80338903,0
"The @GENE$ c.1787A>G (@VARIANT$) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to PiT2 dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the @GENE$ c.317G>C (@VARIANT$) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Three variants were studied further in primary fibroblast cultures (@VARIANT$, c.*108C > T and c.*110G > A). The UTR variants and a known pathogenic exonic FUS variant all cause a mislocalization of the FUS protein, an effect not seen in the other patients or controls. Similarly, the @VARIANT$ variant, found in two subjects with a rapidly progressive form of ALS, increase FUS expression dramatically; overexpression of wild-type @GENE$ causes an ALS-like syndrome in mice. The 3'UTR of @GENE$ is known to be involved in a feedback loop for its own expression via the alternative splicing of exon 7.",5445258,FUS;134091,FUS;2521,c.*59G > A;tmVar:c|SUB|G|*59|A;HGVS:c.*59G>A;VariantGroup:39;CorrespondingGene:2521;RS#:959552367;CA#:280602102,c.*48G > A;tmVar:c|SUB|G|*48|A;HGVS:c.*48G>A;VariantGroup:59;CorrespondingGene:6647,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"(A) Patient with homozygous variants in both ANO5 and @GENE$ genes. NGS reads indicated the identification of homozygous missense pathogenic variants c.2272C>T (@VARIANT$) and c.850C>T (@VARIANT$) in @GENE$ and SGCA genes, respectively.",6292381,SGCA;9,ANO5;100071,p.R758C;tmVar:p|SUB|R|758|C;HGVS:p.R758C;VariantGroup:30;CorrespondingGene:203859;RS#:137854529;CA#:130516,R284C;tmVar:p|SUB|R|284|C;HGVS:p.R284C;VariantGroup:17;CorrespondingGene:6442;RS#:137852623;CA#:120431,0
"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant @GENE$ (p.@VARIANT$, p.A2282T) vector plasmids and myc-tagged WT or mutant @GENE$ (p.R297C, @VARIANT$).",7279190,FLNB;37480,TTC26;11786,R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,0
"This indicates that neither p.R143W in GJB2 nor @VARIANT$ in WFS1 contributed to SNHL in SH60-136 and that @VARIANT$ in @GENE$ was an incidentally detected variant in this subject. GJB2 = gap junction protein beta 2, SNHL = sensorineural hearing loss, @GENE$ = wolfram syndrome 1.",4998745,GJB2;2975,WFS1;4380,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and @GENE$ heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 @VARIANT$ (p.P642R) and SCRIB @VARIANT$ (p.G1108E) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,CELSR1;7665,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,c.3323G > A;tmVar:c|SUB|G|3323|A;HGVS:c.3323G>A;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"A concomitant variant (p.R1193Q, @VARIANT$) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This SCN5A-R1193Q variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).    Gene variants of @GENE$ and @GENE$ identified in the family. (A) Direct sequencing reveals a heterozygous mutation (@VARIANT$, p.Q1916R) in CACNA1C.",5426766,CACNA1C;55484,SCN5A;22738,rs41261344;tmVar:rs41261344;VariantGroup:7;CorrespondingGene:6331;RS#:41261344,c.5747A>G;tmVar:c|SUB|A|5747|G;HGVS:c.5747A>G;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,0
"Variants in all known WS candidate genes (EDN3, @GENE$, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:@VARIANT$; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.",4470809,TBK1;22742,OPTN;11085,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,c.2086G>A;tmVar:c|SUB|G|2086|A;HGVS:c.2086G>A;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"(c) Sequencing chromatograms of the heterozygous mutation c.1787A>G (@VARIANT$) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in PDGFRB (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the @GENE$ variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, p.Tyr27His), MBD5 (NM_018328.4, c.2000T>G, p.Leu667Trp), and @GENE$ (NM_004801.4, @VARIANT$, @VARIANT$), all of which were inherited.",6371743,GAMT;32089,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"The pathogenicity of the @VARIANT$ mutation in @GENE$  is, however, questionable since we found it in five alleles from the control population. The c.5601delAAC mutation in PCDH15, leading to an in frame-deletion of a threonine residue (@VARIANT$) within the intracellular domain of the protocadherin-15 CD1 isoform, also warrants a special mention. Three protocadherin-15 isoforms (CD1-3) that differ in their intracytoplasmic regions have been reported. Already two presumably pathogenic mutations (p.M1853L and p.T1868del) have been found in exon 34 that is specific for CD1. Incidentally, the p.T1868del mutation was not only involved in USH1, but has also been found, in homozygous state, in a deaf patient presenting with vestibular arreflexia and without retinitis pigmentosa (C. Bonnet, unpublished). The CD2 isoform(s) of @GENE$ make(s) the transient kinociliary links, whereas the protocadherin-15 isoforms that make transient interstereocilia links and the tip-links are still unknown.",3125325,CDH23;11142,protocadherin-15;23401,p.T1209A;tmVar:p|SUB|T|1209|A;HGVS:p.T1209A;VariantGroup:132;CorrespondingGene:64072;RS#:41281314;CA#:137387,p.T1868del;tmVar:p|DEL|1868|T;HGVS:p.1868delT;VariantGroup:223;CorrespondingGene:65217,0
"In patient AVM558, a pathogenic heterozygous variant c.920dupA (p.Asn307LysfsTer27) inherited from the mother was identified in @GENE$. Another de novo novel heterozygous missense variant, c.1694G>A (p.Arg565Gln), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling. This de novo variant may modify the effect of the truncating variant in ENG by repressing BMP/TGF-beta signalling. In patient AVM359, one heterozygous VUS (c.589C>T [@VARIANT$]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in SCUBE2 were identified (online supplementary table S2).",6161649,ENG;92,MAP4K4;7442,p.Arg197Trp;tmVar:p|SUB|R|197|W;HGVS:p.R197W;VariantGroup:2;CorrespondingGene:2022;RS#:2229778,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,0
"Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (@VARIANT$, @VARIANT$) and @GENE$ (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of @GENE$ and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN2;86984,NRXN1;21005,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), p.H70fsX5, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,0
"Although, mutations in three genes (MITF, @GENE$, and @GENE$) have been shown to cause WS2 subtypes, a number of cases remain unexplained at the molecular level. Moreover, inter- and intrafamilial phenotypic variability cannot be explained due to mutations in a single gene. Digenic inheritance or modulation of phenotype by modifier genes could possibly explain the variability and expressivity. Therefore, we embarked a genetic study using a large family segregating WS2. SNP genotyping followed by detection of shared regions identified two regions on chromosome 2 and 18. In this study, we sequenced complete exome in two affected individuals and identified candidate variants in MITF (c.965delA), SNAI2 (@VARIANT$) and C2orf74 (@VARIANT$) genes.",7877624,SOX10;5055,SNAI2;31127,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  @GENE$ variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the FUS protein.",6707335,SPG11;41614,FUS;2521,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of @GENE$ and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,PAX3;22494,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Four genes (including AGXT2, @GENE$, @GENE$, TCF4) were found to be related to the PMI related. It turned out to be that only SCAP-c.3035C>T (@VARIANT$) and AGXT2-@VARIANT$ (p.Ala338Val) were predicted to be causive by both strategies.",5725008,ZFHX3;21366,SCAP;8160,p.Ala1012Val;tmVar:p|SUB|A|1012|V;HGVS:p.A1012V;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"The brother who is homozygous (II.4) for the TNFRSF13B/TACI @VARIANT$ mutation has the lowest IgG levels, and consistently generated fewer isotype switched and differentiated ASC in vitro, compared with other family members who are heterozygotes. The presence of concomitant mutations, such as the TCF3 T168fsX191 mutation seen in the proband, may explain the variable penetrance and expressivity of TNFRSF13B/TACI mutations in CVID. Individuals with digenic disorders will pose challenges for preimplantation genetic diagnosis and chorionic villus sampling. Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the @GENE$/TACI C104R mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TNFRSF13B;49320,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,0
   Two nucleotide variants in exon 8 (c.868 G > T; @VARIANT$) of the GCK gene and in exon 4 (@VARIANT$; p.Pro291Arg) of the @GENE$ gene were identified. These variants were confirmed with standard Sanger sequencing. Molecular sequencing extended to the diabetic parents showed that the @GENE$ variant was present in the father and the HNF1A variant was present in the mother (Figure 1B).,8306687,HNF1A;459,GCK;55440,p.Glu290*;tmVar:p|SUB|E|290|*;HGVS:p.E290*;VariantGroup:9;CorrespondingGene:2645,c.872 C > G;tmVar:c|SUB|C|872|G;HGVS:c.872C>G;VariantGroup:2;CorrespondingGene:6927;RS#:193922606;CA#:214336,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Cases A and B carried nonsense mutations in OPTN (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; p.Glu696Lys; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of @GENE$ to @GENE$ in vitro.",4470809,TBK1;22742,OPTN;11085,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
"The proband from Family 1 is consistent with the H1 haplotype based on the presence of homozygous genotypes for rs4935 and rs4797 although this is not definitive because the rs10277 and @VARIANT$ polymorphisms were not covered. The haplotype of the proband from Family 2 could not be determined based on the available genotype data. For Family 3, sequencing data were available for four family members, and we manually reconstructed the haplotype assuming the minimal number of recombinations. The result indicated that Family 3's haplotype was consistent with either the H2 or the H5 haplotype described in the study by Lucas et al.. On the basis of these results, our three families have at least two different haplotypes associated with the SQSTM1 mutation, indicating that this unique phenotype is not a haplotype-specific effect, as well as demonstrating that these families are not remotely related to each other.   Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in @GENE$ (p.Pro392Leu) and a variant in @GENE$ (@VARIANT$).",5868303,SQSTM1;31202,TIA1;20692,rs1065154;tmVar:rs1065154;VariantGroup:2;CorrespondingGene:8878;RS#:1065154,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"To the best of our knowledge, two of the identified variants (@GENE$: c.1183C>A, @VARIANT$; and @GENE$: @VARIANT$, p.(P179T)) have not been previously identified.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: c.4343C > T (@VARIANT$) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants PKHD1: @VARIANT$ (p.R559W) and @GENE$: c.7942G > A (p.G2648S), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,p.S1448F;tmVar:p|SUB|S|1448|F;HGVS:p.S1448F;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,c.1675C > T;tmVar:c|SUB|C|1675|T;HGVS:c.1675C>T;VariantGroup:16;CorrespondingGene:5314;RS#:141384205;CA#:3853488,0
Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the 497A>G (N166S) mutation (d) and WT allele (e) of GJB3. Direct sequence analysis showing the @VARIANT$ (A194T) mutation (i and n) and WT allele (j and o) of GJB3.   Expression of @GENE$ and @GENE$ in the mouse cochlea examined by coimmunostaining Cochlear cryosections were cut at a thickness of 8 mum and labeled with an antibody against Cx26 (a) and Cx31 (b).,2737700,Cx31;7338,Cx26;2975,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,580G>A;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The proband's son (III.1) has inherited the TCF3 @VARIANT$ mutation, but not the TNFRSF13B/TACI @VARIANT$ mutation. The proband's clinically unaffected daughter (III.2) has not inherited either mutation. The TCF3 T168fsX191 mutation was absent in the proband's parents, indicating a de novo origin. (c) Schema of wild-type and truncated mutant @GENE$ T168fsX191 gene. Exons coding E2A functional domains, activation domain 1 and 2 (@GENE$, AD2) and helix-loop-helix (HLH) domains are shown.",5671988,TCF3;2408,AD1;56379,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Furthermore, this @GENE$-@VARIANT$ mutation was absent in 800 chromosomes from 400 healthy controls. A concomitant variant (@VARIANT$, rs41261344) with an allele frequency of 0.006215 (data form ExAC) in SCN5A was also found in the proband (Fig 2D, Table 2). This @GENE$-R1193Q variant, located in a highly conserved spot in the linker region between domains II and III (Fig 2E and 2F), has been reported to be ""gain-of-function"" and associated with long QT syndrome (LQTS).",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,p.R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, p.Ser127Thr; @VARIANT$, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,g.124339A>G;tmVar:g|SUB|A|124339|G;HGVS:g.124339A>G;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (@GENE$ @VARIANT$ and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare @GENE$ missense variant @VARIANT$ and a novel FAT4 missense variant c.10147G>A).",5887939,FZD6;2617,FZD1;20750,c.544G>A;tmVar:c|SUB|G|544|A;HGVS:c.544G>A;VariantGroup:0;CorrespondingGene:8323;RS#:147788385;CA#:4834818,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, @VARIANT$; and PITX2: c.535C>A, @VARIANT$) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: p.(C498R) and p.(H395N); PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), @GENE$ (@VARIANT$; p.L16V) and USH2A (c.9921T>G).",3125325,CDH23;11142,USH1G;56113,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"Taken together, pathological @GENE$ variants were found in 15.8% of ICP cases (Table S1 ). Rare CTRC genotypes contributed to the development of ICP in 4.3% of cases  CTRC has conventionally been regarded as being the least important gene in terms of a genetic predisposition to chronic pancreatitis, as compared with PRSS1 and SPINK1. This view received further support from two recent developments. First, some of the CTRC variants characterized by a complete or virtually complete functional loss of the affected alleles, exemplified by p.K247_R254del and p. G217S, have been reported in unrelated healthy controls. Second, whereas a heterozygous CTRC whole gene deletion was found in trans with other genetic predisposing alleles in two subjects with familial chronic pancreatitis, a different homozygous CTRC whole gene deletion was identified in a patient with asymptomatic ICP. Employing the functionally null CTRC allele, p.K247_@VARIANT$, which increases the risk of ICP 6.4-fold, as a reference (N.B. the heterozygous SPINK1 @VARIANT$ allele confers a >10-fold increased risk), any loss-of-function variants in the @GENE$ gene may at most be interpreted as disease-predisposing.",3738529,SPINK1;68300,CTRC;21422,R254del;tmVar:p|DEL|254|R;HGVS:p.254delR;VariantGroup:21;CorrespondingGene:11330,p. N34S;tmVar:p|SUB|N|34|S;HGVS:p.N34S;VariantGroup:7;CorrespondingGene:6690;RS#:17107315;CA#:123440,0
"Sequencing of Case 7 revealed a heterozygous c.1183_1185delGAG non-frameshift variation in exon 7 that leads to the deletion of amino acid 395 (@VARIANT$) in the LBD of the protein. This variant was also found in the mother of the patient. Except for Case 4, DNA samples of patients, in which only a single gene approach had been performed initially, were further analyzed by the targeted DSD gene panel including 48 genes. Additional heterozygous variants in known DSD genes were found in three out of six (50%) 46,XY DSD NR5A1 carriers. For Case 1, a novel missense VUS (variant of unknown significance) variant (c.361C>T; p.Arg121Trp) in the @GENE$ gene was identified in the patient and his father. A rare variant in AMH, c.428C>T; p.Thr143Ile, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported @GENE$/FOG2 (@VARIANT$; p.Met544Ile) pathogenic missense alteration was identified.",7696449,STAR;297,ZFPM2;8008,p.Glu395del;tmVar:p|DEL|395|E;HGVS:p.395delE;VariantGroup:6;CorrespondingGene:1113,c.1632G>A;tmVar:c|SUB|G|1632|A;HGVS:c.1632G>A;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of @VARIANT$. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of @GENE$ (NM_007123), R5143C, @VARIANT$, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and Ankyrin 1 (@GENE$) identified in SH 94-208).",4998745,USH2A;66151,ANK1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,C4870F;tmVar:p|SUB|C|4870|F;HGVS:p.C4870F;VariantGroup:24;CorrespondingGene:7399,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in SLC20A2 (Figure 1c) and NM_002609.4, exon3, @VARIANT$, p.Arg106Pro, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the @GENE$ mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a).",8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with @GENE$ @VARIANT$ while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and TAF15 p.R408C with SETX p.I2547T and @GENE$ @VARIANT$).",4293318,VAPB;36163,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,0
"A rare variant in @GENE$, c.428C>T; @VARIANT$, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/@GENE$ (c.1632G>A; @VARIANT$) pathogenic missense alteration was identified.",7696449,AMH;68060,FOG2;8008,p.Thr143Ile;tmVar:p|SUB|T|143|I;HGVS:p.T143I;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,p.Met544Ile;tmVar:p|SUB|M|544|I;HGVS:p.M544I;VariantGroup:1;CorrespondingGene:23414;RS#:187043152;CA#:170935,0
"In patient IID27, we detected a de novo mutation in @GENE$ combined with a COL4A4 mutation. The female patient presents a severe phenotype, showing hematuria, proteinuria, and CKD. Her mother with c.1339 + 3A>T in COL4A5 and her father with a missense mutation c.4421C > T in COL4A4 had intermittent hematuria and proteinuria. In proband of family 29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation @VARIANT$ in @GENE$ genes.",6565573,COL4A5;133559,COL4A4;20071,Gly1119Ala;tmVar:p|SUB|G|1119|A;HGVS:p.G1119A;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,c.5026C > T;tmVar:c|SUB|C|5026|T;HGVS:c.5026C>T;VariantGroup:20;CorrespondingGene:1286,0
"Therefore, in this study, @GENE$ @VARIANT$ may be the main cause of sinoatrial node dysfunction, whereas @GENE$ @VARIANT$ only carried by II: 1 may potentially induce the phenotype of LQTS.",8739608,SCN5A;22738,KCNH2;201,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,1
"The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene. Variants in the @GENE$ gene result in impairment of retrograde axonal transport leading to progressive motor neuron degeneration in mice and have been described in a range of neurogenetic diseases, including Charcot-Marie-Tooth type 2O, spinal muscular atrophy, and hereditary spastic paraplegia. A few studies described heterozygous variants in the DYNC1H1 gene in fALS and sALS patients, suggesting its role in ALS. Based on our findings, we strengthen the potential link between DYNC1H1 variants and ALS.     Given that there are genetic and symptomatic overlaps among many neurodegenerative diseases, it has been suggested that causative variants might play roles in multiple disorders. Two heterozygous variants (H398R and @VARIANT$) were detected in the GBE1 gene.",6707335,MATR3;7830,DYNC1H1;1053,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,R166C;tmVar:p|SUB|R|166|C;HGVS:p.R166C;VariantGroup:21;CorrespondingGene:2632;RS#:376546162;CA#:2499951,0
"The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of WNT10A showed a @VARIANT$, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous @GENE$ and @GENE$ mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes.     ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90.",3842385,EDA;1896,WNT10A;22525,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,0
"(c) Sequencing chromatograms of the heterozygous mutation @VARIANT$ (p.His596Arg) in SLC20A2. (d) Sequencing chromatograms of the heterozygous mutation c.317G>C (p.Arg106Pro) in PDGFRB     Genomic DNA was extracted from peripheral blood, and the DNA sample of the proband was subjected to screen the known causative genes for PFBC. Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, c.1787A>G, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, p.Arg106Pro, @VARIANT$ in @GENE$ (Figure 1d).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the @GENE$ protein, which is involved in binding to proteasome subunits.",6707335,SPG11;41614,ubiquilin-2;81830,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The @VARIANT$ (c.936C>G) mutation in EDA and heterozygous p.Arg171Cys (@VARIANT$) mutation in WNT10A were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of Ile at residue 312 to Met; also, the coding sequence in exon 3 of @GENE$ showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome revealed that the mutant alleles were from his mother, who carried digenic heterozygous EDA and WNT10A mutations at the same locus as that of N2 (Fig. 2B). Clinical examination showed that maxillary lateral incisors on both sides and the left mandibular second molar were missing in the mother, but there were no anomalies in other organs. The father did not have any mutations for these genes.     ""S1"" is a 14-year-old boy who had 21 permanent teeth missing (Table 1). The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90.",3842385,WNT10A;22525,EDA;1896,p.Ile312Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Detection of mutations Screening of the WNT10A, EDA, @GENE$, and EDARADD genes was performed by direct sequencing of five PCR fragments for WNT10A, eight PCR fragments for EDA, ten PCR fragments for EDAR, and eight PCR fragments for EDARADD, which cover the entire cDNA including exons and intron-exon junctions of more than 100 base pairs. We compared all primer sequences to the whole-genome assembly in the ENSEMBL database to verify their uniqueness against gene families. Primer sequences are available upon request. Protein structure analysis We performed protein structure analysis on the two @GENE$ mutations (@VARIANT$ and p.G213S) and two novel EDA mutations (p.G257R and @VARIANT$) that were identified in this study.",3842385,EDAR;7699,WNT10A;22525,p.R171C;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,p.I312M;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"Six potentially oligogenic subjects had a family history of ALS subjects and in all cases one of their variants was either the C9ORF72 repeat expansion or a missense variant in @GENE$ in combination with additional rare or novel variant(s), several of which have also been previously reported in ALS subjects. Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 @VARIANT$, ANG p.P136L, and DCTN1 p.T1249I. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.G38R;tmVar:p|SUB|G|38|R;HGVS:p.G38R;VariantGroup:50;CorrespondingGene:6647;RS#:121912431;CA#:257311,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in @GENE$ play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in MYH7 (L1038P) and MYBPC3 (@VARIANT$), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and @GENE$ (@VARIANT$), both sarcomeric genes.",6359299,LAMA4;37604,TNNT2;68050,R326Q;tmVar:p|SUB|R|326|Q;HGVS:p.R326Q;VariantGroup:6;CorrespondingGene:4607;RS#:34580776;CA#:16212,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"It was shown that digenic variants in @GENE$ and @GENE$ contribute to PCG and that variants in both FOXC1 and PITX2 are responsible for some cases of ARS. This prompted us to explore the frequency of CHD in patients with ARS carrying a Foxc1 mutation and whether or not there is a need to carry on WES to investigate the role of other variants in conjunction with FOXC1 that would explain these cardiac defects. Whole Exome Sequencing A tool to draw genotype-phenotype correlation out of the 67 FOXC1 variants reported so far to be linked to the ARS, only nine have been shown to be linked to cardiac defects in addition to the ocular defects. A scrutinized review of the literature of these nine variants, namely p.Q70Hfs*8, p.P79T, p.S82T, @VARIANT$, @VARIANT$, p.F112S, p.R127L, p.G149D, and p.R170W, did show that the cardiac phenotype with which they are associated is not as clear as it is presumed.",5611365,CYP1B1;68035,MYOC;220,p. A85P;tmVar:p|SUB|A|85|P;HGVS:p.A85P;VariantGroup:78;CorrespondingGene:6012,p.L86F;tmVar:p|SUB|L|86|F;HGVS:p.L86F;VariantGroup:6;CorrespondingGene:2296;RS#:886039568;CA#:10588416,0
"Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; p.Ile346Asn) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, RNF43, APC, ZNRF3, @GENE$, LRP5, @GENE$, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well. No potentially pathogenic rare variant was identified. In order to identify variant(s) in other genes which might influence the expressivity of WS phenotype in our cases, exome data was filtered by using an unbiased and hypothesis-free approach. A rare missense variant (@VARIANT$; p.Val34Gly) in the C2orf74 gene was identified in both affected individuals.",7877624,LRP4;17964,LRP6;1747,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,SOX10;5055,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d). Genotyping analysis revealed that the GJB2/235delC was inherited from the unaffected father and the @VARIANT$ of @GENE$ was inherited from the normal hearing mother (Fig. 1a).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2. Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and TAF15 p.R408C with SETX p.I2547T and @GENE$ p.T14I).",4293318,TARDBP;7221,SETX;41003,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,SOX10;5055,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Only three variants were homozygous in three patients: (1) @GENE$: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) @GENE$: c.413dupA (@VARIANT$) in one patient.",6098846,DUOX2;9689,DUOXA2;57037,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"The mother and the father were asymptomatic carriers of @GENE$: c.4437_4440delCATA (p.F1479Lfs*20) and PKHD1: @VARIANT$ (p.G1979R), respectively (Figure 3).      The foetuses in Family 24 and Family 25 appeared to have additional symptoms besides PKD. The couple from Family 24 had undergone abortion three times due to phenotypes similar to those in renal cystic disorders, bladder dysplasia and oligohydramnios. The sample of the third pregnancy was subjected to genetic testing using WES plus Sanger sequencing. The compound heterozygous variants of TMEM67: c.637C > T (p.R213C) and TMEM67: @VARIANT$ (p.G195Dfs*27) were identified and likely agreed with the Meckel Gruber syndrome type 3 (@GENE$, MIM #607316), which segregated from the asymptomatic parents (Figure 3).",8256360,PKHD1;16336,MKS3;71886,c.5935G > A;tmVar:c|SUB|G|5935|A;HGVS:c.5935G>A;VariantGroup:1;CorrespondingGene:5314,c.579delA;tmVar:c|DEL|579|A;HGVS:c.579delA;VariantGroup:5;CorrespondingGene:91147;RS#:386834203(Expired),0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, @VARIANT$, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations. The @GENE$ @VARIANT$ and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"The @VARIANT$ variant in @GENE$ occurring in complex heterozygosity with a pathogenic @GENE$ variant, @VARIANT$ from SH175-389, suggests a possible digenic etiology of SNHL involving two different gap junction proteins, Cx26 and Cx31.",4998745,GJB2;2975,GJB3;7338,p.V193E;tmVar:p|SUB|V|193|E;HGVS:p.V193E;VariantGroup:21;CorrespondingGene:2706,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"In fact, the two @GENE$ amino acid changes were found to be hypomorphic whereas the @GENE$ amino acid substitution (p.(P179T)) behaved experimentally as a hypermorphic variant. Additional structural and functional analysis indicated that p.(H395N) alters polypeptide chain conformation and decreases protein stability, which can explain the associated reduced transactivation. However, our data showed that the transactivation effect of @VARIANT$ is not due either to altered protein stability, protein structure or subcellular localization, suggesting that the substitution of a basic (arginine) for a polar (cysteine) amino acid may disrupt protein interactions in the second inhibitory domain of the protein, leading to reduced protein activity. Similarly, our results indicate that increased transactivation associated with the @VARIANT$ PITX2 mutation is not related with altered protein stability, protein conformation or subcellular localization.",6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.P179T;tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (@VARIANT$; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,c.757G>A;tmVar:c|SUB|G|757|A;HGVS:c.757G>A;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, @GENE$-@VARIANT$ and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas @GENE$-@VARIANT$, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, @GENE$, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,SOX10;5055,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; @VARIANT$ of NELF and c.488_490delGTT; p.Cys163del of KAL1) and @GENE$/TACR3 (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of @GENE$).,3888818,NELF;10648,TACR3;824,p.Ala253Thr;tmVar:p|SUB|A|253|T;HGVS:p.A253T;VariantGroup:3;CorrespondingGene:26012;RS#:142726563;CA#:5370407,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (CCDC88C @VARIANT$). Considering the facts that the loss-of-function mutations in @GENE$ were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.",8152424,DCC;21081,FGFR1;69065,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"    In patient AVM144, the compound heterozygous variants c.116-1G>A and c.1000T>A (p.Ser334Thr) were identified in @GENE$ (table 2).   Potential oligogenic inheritance Variants in more than one gene (at least one likely pathogenic variant) with differing inheritance origin were identified in three patients (figure 1). In patient AVM558, a pathogenic heterozygous variant @VARIANT$ (p.Asn307LysfsTer27) inherited from the mother was identified in ENG. Another de novo novel heterozygous missense variant, c.1694G>A (@VARIANT$), was identified in @GENE$ (online supplementary table S2), which encodes the kinase responsible for phosphorylation of residue T312 in SMAD1 to block its activity in BMP/TGF-beta signalling.",6161649,PTPN13;7909,MAP4K4;7442,c.920dupA;tmVar:c|DUP|920|A|;HGVS:c.920dupA;VariantGroup:12;CorrespondingGene:2022,p.Arg565Gln;tmVar:p|SUB|R|565|Q;HGVS:p.R565Q;VariantGroup:5;CorrespondingGene:9448;RS#:1212415588,0
"Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 @GENE$ missense variants @VARIANT$; c.10384A>G), and 465F99 (rare @GENE$ missense variant @VARIANT$ and a novel FAT4 missense variant c.10147G>A).",5887939,FAT4;14377,FZD1;20750,c.5792A>G;tmVar:c|SUB|A|5792|G;HGVS:c.5792A>G;VariantGroup:2;CorrespondingGene:79633;RS#:373263457;CA#:4677776,c.211C>T;tmVar:c|SUB|C|211|T;HGVS:c.211C>T;VariantGroup:8;CorrespondingGene:8321;RS#:574691354;CA#:4335060,0
"These phenomenon indicate that the mutated @GENE$-@VARIANT$ (p.Ala1012Val) protein failed to sensing the intracellular cholesterol level, implying a loss of negative feedback mechanism of the mutated SCAP coding protein. @GENE$-@VARIANT$ (p.Ala338Val) variant impaired the catabolism of ADMA in EA.",5725008,SCAP;8160,AGXT2;12887,c.3035C>T;tmVar:c|SUB|C|3035|T;HGVS:c.3035C>T;VariantGroup:2;CorrespondingGene:22937,c.1103C>T;tmVar:c|SUB|C|1103|T;HGVS:c.1103C>T;VariantGroup:3;CorrespondingGene:64902;RS#:536786734;CA#:116921745,0
"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, @VARIANT$) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and @GENE$ variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1alpha/2alpha knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"Similarly, patients 8 and 10 both had a combination of a known truncating mutation (p.K530X) and a known inactivating mutation (@VARIANT$ or @VARIANT$); one exhibited permanent CH and one showed transient hypothyroidism. Furthermore, patient 7 had exactly the same mutations as patient 8, and her prognosis was unknown. Unlike patient 8, who had a goiter, patient 7's thyroid size was normal. Moreover, numbers of detected variants differed among patients who shared the same phenotypes. 4. Discussion Thyroid hormone biosynthesis defects are common causes of CH. Mutations in DH-associated genes, including TPO, TG, @GENE$, @GENE$, SLC26A4, SCL5A5, and IYD, have been detected in numerous cases.",6098846,DUOX2;9689,DUOXA2;57037,p.R110Q;tmVar:p|SUB|R|110|Q;HGVS:p.R110Q;VariantGroup:29;CorrespondingGene:7173;RS#:750143029;CA#:1511376,p.R885Q;tmVar:p|SUB|R|885|Q;HGVS:p.R885Q;VariantGroup:18;CorrespondingGene:50506;RS#:181461079;CA#:7538197,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 @VARIANT$ and GFP-@GENE$ E229K to immunoprecipitate HA-@GENE$ @VARIANT$ and HA-TEK Q214P, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"a, b Pedigree chart of the patients carrying mono-allelic @GENE$ and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 p.T410M mutations. The arrow indicates the vestibular aqueduct in the patient and the healthy control. Among sensorineural hearing loss patients EVA or the Pendred syndrome patients, a considerable number of patients carry one copy of the mutation on the @GENE$ gene, therefore a compromised pendrin regulatory machinery may be involved in the pathogenesis of the syndrome.",7067772,EPHA2;20929,SLC26A4;20132,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Moreover, the MAF of KCNQ1-p.@VARIANT$ was much smaller (0.000016) than the estimated prevalence of LQTS (0.0005), whereas the MAFs of KCNH2-p.K897T and @GENE$-p.G38S were much larger (0.187 and 0.352, respectively). @GENE$-p.@VARIANT$ is not reported in the ExAC database.",5578023,KCNE1;3753,KCNH2;201,R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare @GENE$ (GLDC) c.2203G>T missense variant, possibly indicating a compromised FOCM in this patient. Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (c.7549G>A; @VARIANT$) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (CELSR1) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3).",5887939,MTHFR;4349,glycine decarboxylase;141,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,p.Val2517Met;tmVar:p|SUB|V|2517|M;HGVS:p.V2517M;VariantGroup:14;CorrespondingGene:9620;RS#:1261513383,0
"Furthermore, @GENE$ presented 2 variants in patient 1. Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and @GENE$ variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,RIPK4;10772,MAML3;41284,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
    CSS170323 carries a heterozygous missense variant c.630G>C(@VARIANT$) in @GENE$ and a heterozygous missense variant c.190G>A(@VARIANT$) in @GENE$ (Table 2).,7549550,MYOD1;7857,MEOX1;3326,p.Met210Ile;tmVar:p|SUB|M|210|I;HGVS:p.M210I;VariantGroup:9;CorrespondingGene:4654;RS#:749634841;CA#:5906491,p.Ala64Thr;tmVar:p|SUB|A|64|T;HGVS:p.A64T;VariantGroup:5;CorrespondingGene:4222;RS#:373680176;CA#:8592682,1
"We identified a novel variant in BBS1 patient #10 c.1285dup (@VARIANT$) defined as pathogenic that segregates with phenotype together with c.46A > T (p.(Ser16Cys), defined as likely pathogenic.     A new pathogenic variant in BBS2 affecting a conserved residue in the functional domain of BBsome protein (c.1062C > G; p.(Asn354Lys)) was found in compound heterozygous state in patient #1 together with the known pathogenic variant p.(Arg339*). A new homozygous nucleotide change in BBS7 that leads to a @VARIANT$, c.763A > T, was identified in patient #3. BBS1, BBS2 and @GENE$ share a partially overlapping portion of a functional domain, mutation of which results in the same disease phenotype. New pathogenic variants of @GENE$ and BBS7 lie in this portion.",6567512,BBS7;12395,BBS2;12122,"p.(Arg429Profs*72);tmVar:p|FS|R,P|429|RO|72;HGVS:p.R,P429ROfsX72;VariantGroup:28;CorrespondingGene:582",stop codon in position 255;tmVar:p|Allele|X|255;VariantGroup:1;CorrespondingGene:79738;RS#:139658279,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"No mutations in @GENE$, @GENE$, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,SLC5A5;37311,TPO;461,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (@VARIANT$) and a heterozygous WNT10A @VARIANT$ mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, @VARIANT$), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, @VARIANT$), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,ATP2A3;69131,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"In patient AVM359, one heterozygous VUS (c.589C>T [p.Arg197Trp]) in ENG inherited from the mother and one likely pathogenic de novo heterozygous variant (c.1592G>A [@VARIANT$]) in @GENE$ were identified (online supplementary table S2). SCUBE2 functions as a coreceptor that enhances VEGF/VEGFR2 binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,SCUBE2;36383,TIMP3;36322,p.Cys531Tyr;tmVar:p|SUB|C|531|Y;HGVS:p.C531Y;VariantGroup:5;CorrespondingGene:57758;RS#:1212415588,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of @GENE$) and NELF/@GENE$ (@VARIANT$ of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,KAL1;55445,TACR3;824,c. 1160-13C>T;tmVar:c|SUB|C|1160-13|T;HGVS:c.1160-13C>T;VariantGroup:5;CorrespondingGene:26012;RS#:781275840;CA#:5370137,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"@GENE$-p.C108Y homozygous tetramers and KCNH2-WT/KCNH2-@VARIANT$ heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx31;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Deleterious variants in @GENE$ (NM_022460.3: @VARIANT$, p.Gly32Cys) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,UNC13B,@GENE$,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,SPTBN4;11879,c.94C>A;tmVar:c|SUB|C|94|A;HGVS:c.94C>A;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"   A male (ID041), unrelated to ID104, carried heterozygous missense variants @VARIANT$ (p.Gly505Ser) in @GENE$ and c.353A > G (@VARIANT$) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,c.1513G > A;tmVar:c|SUB|G|1513|A;HGVS:c.1513G>A;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,p.Asn118Ser;tmVar:p|SUB|N|118|S;HGVS:p.N118S;VariantGroup:5;CorrespondingGene:256471;RS#:774112195;CA#:3077496,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Moreover, patients carrying a @GENE$ @VARIANT$ mutation have a significantly reduced extracellular matrix (ECM) in cardiomyocytes. These findings support the importance of LAMA4 as a structural and signalling molecule in cardiomyocytes, and may indicate the modifier role that missense variations in LAMA4 play in the disease. Digenic heterozygosity has been described in some DCM cases and is often associated with a severe presentation of DCM. Moller et al. reported an index case with digenic variants in @GENE$ (@VARIANT$) and MYBPC3 (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated.",6359299,LAMA4;37604,MYH7;68044,Pro943Leu;tmVar:p|SUB|P|943|L;HGVS:p.P943L;VariantGroup:5;CorrespondingGene:3910;RS#:387907365;CA#:143749,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,0
"In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in @GENE$ inherited from the father and one likely pathogenic de novo novel heterozygous variant (c.311T>C [@VARIANT$]) in @GENE$ were identified (online supplementary table S2).",6161649,RASA1;2168,TIMP3;36322,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,p.Leu104Pro;tmVar:p|SUB|L|104|P;HGVS:p.L104P;VariantGroup:7;CorrespondingGene:23592;RS#:1290872293,1
"However, one patient had a @GENE$ mutation on one of the alleles (@VARIANT$), but no mutation on the other allele. Other monoallelic mutations of GNRHR have been reported in patients with CHH and have challenged the traditional view of GNRHR as a recessive gene. It has been suggested that such patients with monoallelic mutations may have additional mutations in other genes that act synergistically to produce the phenotype. To explore this possibility, we screened this patient for mutations in other commonly implicated genes in CHH and identified an additional heterozygous missense mutation (@VARIANT$) in the @GENE$ gene.",5527354,GNRHR;350,PROKR2;16368,p.Val134Gly;tmVar:p|SUB|V|134|G;HGVS:p.V134G;VariantGroup:1;CorrespondingGene:2798;RS#:188272653;CA#:2938946,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,1
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and @GENE$ @VARIANT$ mutations on @GENE$ interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the @VARIANT$ mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f).",7067772,pendrin;20132,EphA2;20929,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"To investigate the role of @GENE$ variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel @VARIANT$ of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A to G transition at nucleotide position 497;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"The co-occurrence of @GENE$ and @GENE$ mutations in one family raised the possibility of digenic inheritance. Enamel formed in Enam+/+Ambn +/+, Enam+/-, Ambn+/-, and Enam+/-Ambn+/- mice was characterized by dissection and backscattered scanning electron microscopy (bSEM).           Results  ENAM mutations segregating with AI in five families were identified. Two novel ENAM frameshift mutations were identified. A single-nucleotide duplication (@VARIANT$/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (@VARIANT$/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*).",6785452,ENAM;9698,LAMA3;18279,c.395dupA;tmVar:c|DUP|395|A|;HGVS:c.395dupA;VariantGroup:18;CorrespondingGene:13801,c.2763delT;tmVar:c|DEL|2763|T;HGVS:c.2763delT;VariantGroup:0;CorrespondingGene:10117;RS#:529979202,0
"Quantification of cells with dilated endoplasmic reticulum (ER) and COPII vesicles associated with Golgi by transmission electron microscopy Genotype of cell line Cells with dilated ER (%) Cells with Golgi-associated vesicles (%) Wt (N = 414) 2 (0.5) 309 (75) SEC23Ac.1200G>C/+ (N = 83) 83 (100***) 9 (11***) SEC23Ac.@VARIANT$/+ MAN1B1c.1000C>T/+ (N = 190) 190 (100***) 3 (1.6***) SEC23Ac.1200G>C/c.1200G>C; MAN1B1@VARIANT$/c.1000C>T (N = 328) 328 (100***) 2 (0.6***)  Increased Intracellular and Secreted Pro-COL1A1 in Fibroblasts with Homozygous Mutations in Both @GENE$ and @GENE$ in the Presence of l-Ascorbic Acid SEC23A is required for normal transport of pro-COL1A1, a major extracellular matrix component of bone.",4853519,SEC23A;4642,MAN1B1;5230,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"In Family 4, the @GENE$ @VARIANT$ mutation caused a severe generalized enamel hypoplasia and localized pitting, so the potential contribution of the LAMA3 defect to the enamel phenotype in this family is unclear. The low frequency of the defect and the prediction software results indicate that the heterozygous @GENE$ c.1559G>A/@VARIANT$ mutation would likely cause AI, but such evidence is not decisive by itself (Miosge et al., 2015), so the enamel pathogenicity of this LAMA3 defect remains uncertain.",6785452,ENAM;9698,LAMA3;18279,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and @VARIANT$/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that @GENE$ and @GENE$ have overlapping expression patterns in the cochlea.",2737700,Cx26;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Except for the SEMA7A gene variant [p.(Glu436Lys)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the DUSP6 gene variant [p.(@VARIANT$)]. Such findings bring into question their involvement in disease expression in HH12. The SEMA7A variant [p.(@VARIANT$)] was predicted as VUS by Varsome. Sanger validation revealed the absence of this mutation in the healthy mother. The @GENE$ and @GENE$ genes were implicated in a digenic combination classified as ""dual molecular diagnosis"" by ORVAL.",8446458,SEMA7A;2678,DUSP6;55621,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"Among these four mutations, while the c.503T>G variant in LRP6 is not listed in the databases, the other three are rare sequence variants with respective MAFs of 0.0114 (@GENE$ c.2450C>G, rs2302686), 0.0007 (LRP6 c.4333A>G, rs761703397), and 0.0284 (WNT10A c.637G>A, rs147680216) in EAS. The novel LRP6 c.503T>G mutation substitutes the hydrophobic methionine168 for an arginine (@VARIANT$) and is predicted to be ""probably damaging"", with a PolyPhen-2 score of 1. The other two LRP6 variants, c.2450C>G (p.Ser817Cys) and c.4333A>G (p.Met1445Val), were considered to be ""possibly damaging"" and ""benign"", having PolyPhen-2 scores of 0.723 and 0, respectively. On the other hand, the @GENE$ mutation (@VARIANT$) is well documented to cause tooth agenesis with incomplete penetrance.",8621929,LRP6;1747,WNT10A;22525,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (@VARIANT$, S275N) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:@VARIANT$; p.Gln235*), and TBK1 (NM_013254.3:@VARIANT$; p.Arg117*) respectively; while the other 3 @GENE$ mutations observed in cases C-E were missense changes.",4470809,OPTN;11085,TBK1;22742,c.703C>T;tmVar:c|SUB|C|703|T;HGVS:c.703C>T;VariantGroup:16;CorrespondingGene:10133;RS#:1371904281,c.349C>T;tmVar:c|SUB|C|349|T;HGVS:c.349C>T;VariantGroup:3;CorrespondingGene:29110;RS#:757203783;CA#:6668769,0
"To the best of our knowledge, two of the identified variants (FOXC2: c.1183C>A, p.(H395N); and PITX2: @VARIANT$, p.(P179T)) have not been previously identified. Examination of the genotype-phenotype correlation in this group suggests that the presence of the infrequent PITX2 variants increase the severity of the phenotype. Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and p.(H395N); PITX2: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and @GENE$ variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,FOXC2;21091,PITX2;55454,c.535C>A;tmVar:c|SUB|C|535|A;HGVS:c.535C>A;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,0
"Most had @GENE$ repeat expansion combined with another mutation (e.g. VCP @VARIANT$ or TARDBP A321V; Supplementary Table 6). A single control also had two mutations, P372R in @GENE$ and @VARIANT$ in TARDBP.",5445258,C9orf72;10137,ALS2;23264,R155H;tmVar:p|SUB|R|155|H;HGVS:p.R155H;VariantGroup:10;CorrespondingGene:7415;RS#:121909329;CA#:128983,A90V;tmVar:p|SUB|A|90|V;HGVS:p.A90V;VariantGroup:40;CorrespondingGene:23435;RS#:80356715;CA#:586343,0
"Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC p. Gln91Arg) and a maternal variant (@GENE$ @VARIANT$).",8152424,CHD7;19067,CCDC88C;18903,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"  Recently, Gifford et al., identified three missense variants in @GENE$ (@VARIANT$), MYH7 (@VARIANT$), and @GENE$ (Ala119Ser) in three offspring with childhood-onset cardiomyopathy (Gifford et al., 2019).",7057083,MKL2;40917,NKX2-5;1482;4824,Gln670His;tmVar:p|SUB|Q|670|H;HGVS:p.Q670H;VariantGroup:2;CorrespondingGene:57496,Leu387Phe;tmVar:p|SUB|L|387|F;HGVS:p.L387F;VariantGroup:4;CorrespondingGene:4625,0
Two unrelated KS patients had heterozygous @GENE$ mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and @VARIANT$; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,VPS13C,@GENE$,SPTBN4,@GENE$, and MRPL15 were found in two or more independent pedigrees.",6081235,UNC13B;31376,MYOD1;7857,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
The @GENE$-p.R583H variant was previously reported to be associated with LQTS; KCNH2-p.C108Y is a novel variant; and KCNH2-@VARIANT$ and @GENE$-@VARIANT$ were reported to influence the electrical activity of cardiac cells and to act as modifiers of the KCNH2 and KCNQ1 channels.,5578023,KCNQ1;85014,KCNE1;3753,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"Here, we have demonstrated that the @GENE$ @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the @GENE$/TACI @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family.",5671988,TCF3;2408,TNFRSF13B;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,1
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in @GENE$ by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"KCNH2-@VARIANT$ homozygous tetramers and @GENE$-WT/KCNH2-p.C108Y heterotetramers probably contribute less to the repolarizing current during action potentials and could affect the length of the QT interval. Moreover, the presence of other variants (@GENE$-p.R583H, KCNH2-p.K897T, and KCNE1-@VARIANT$) could further enhance the effects of the mutant channels, thus resulting in incomplete penetrance and variable expressivity of the phenotype.",5578023,KCNH2;201,KCNQ1;85014,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
  LIMITATIONS Our study was performed only in the statistical field on @GENE$ @VARIANT$ and SCN5A p.R1865H by WES and predisposing genes analyses. More cellular and animal research is needed to further investigate whether the coexisting interaction of KCNH2 p.307_308del and @GENE$ @VARIANT$ increases the risk of the early-onset LQTS and sinoatrial node dysfunction.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"We have screened 108 @GENE$ heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB2;2975,GJB3;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In family 18287 we detected a possible bilineal inheritance, with variants in both @GENE$ and @GENE$ (Figure 1). Two pregnancies were interrupted due to a prenatal finding of polycystic kidney disease at ultrasound examination at 20 and 13 gestational weeks, respectively. The mother was 33 year old; she had multicystic bilateral disease without affected family members, and showed a de novo missense variant p.(@VARIANT$) in PKD2. The father was a healthy 44 years old man with no signs of kidney cystic disease at ultrasound, and showed a variant in PKD1, p.(Ser123Thr), and a second variant in PKD2, p.(Arg872Gly). Both fetuses inherited the maternal PKD2 missense variant, in addition to the paternal p.(@VARIANT$) variant in PKD1, while only one fetus inherited the p.(Arg872Gly) PKD2 variant.",7224062,PKD1;250,PKD2;20104,Cys331Thr;tmVar:p|SUB|C|331|T;HGVS:p.C331T;VariantGroup:1;CorrespondingGene:23193;RS#:144118755;CA#:6050907,Ser872Gly;tmVar:p|SUB|S|872|G;HGVS:p.S872G;VariantGroup:9;CorrespondingGene:5311;RS#:755226061,1
"Recurrent Variants Identified in Our Regressive Autism Cohort In our sequenced cohort of 134 individuals with autism and regression, we identified two recurrent variants, GRIN2A c.28C > A (@VARIANT$) and @GENE$ c.742C > T (@VARIANT$). The variant in @GENE$ was novel and was predicted to be damaging using both SIFT and PolyPhen.",7463850,PLXNB2;66630,GRIN2A;645,p.Leu10Met;tmVar:p|SUB|L|10|M;HGVS:p.L10M;VariantGroup:0;CorrespondingGene:2903,p.Arg248Cys;tmVar:p|SUB|R|248|C;HGVS:p.R248C;VariantGroup:9;CorrespondingGene:23654;RS#:779647430;CA#:10313520,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene. The novel Q84H variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,DNAH17;72102,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Coimmunoprecipitation analysis indicated an interaction between wild-type OFD1 and wild-type FLNB, which did not exist between @VARIANT$ @GENE$ and @VARIANT$ OFD1 (figure 3D).  FLNB and @GENE$ variants in individuals with AIS. (A) Pedigree of AIS twins.",7279190,FLNB;37480,OFD1;2677,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Here, we have demonstrated that the TCF3 @VARIANT$ mutation has a more detrimental effect on the phenotype in this pedigree. It could be argued that the TNFRSF13B/@GENE$ @VARIANT$ mutation has a modifying effect on the phenotype and is relatively benign in this family. Hence, priority should be given to identifying the @GENE$ T168fsX191 mutation for preimplantation genetic diagnosis and/or chorionic villus sampling.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"        Ebermann et al. described a USH2 patient with ""digenic inheritance."" a heterozygous truncating mutation in GPR98, and a truncating heterozygous mutation in PDZ domain-containing 7 (@GENE$), which is reported to be a cause of USH. Our USH1 patient (Case #4) had segregated MYO7A:@VARIANT$ and @GENE$:@VARIANT$. Molecular analyses in mouse models have shown many interactions among the USH1 proteins.",3949687,PDZD7;129509,PCDH15;23401,p.Ala771Ser;tmVar:p|SUB|A|771|S;HGVS:p.A771S;VariantGroup:2;CorrespondingGene:4647;RS#:782384464;CA#:10576351,c.158-1G>A;tmVar:c|SUB|G|158-1|A;HGVS:c.158-1G>A;VariantGroup:18;CorrespondingGene:65217;RS#:876657418;CA#:10576348,0
"Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31 Mutations in the genes coding for connexin 26 (@GENE$) and @GENE$ (Cx31) cause non-syndromic deafness. Here, we provide evidence that mutations at these two connexin genes can interact to cause hearing loss in digenic heterozygotes in humans. We have screened 108 GJB2 heterozygous Chinese patients for mutations in GJB3 by sequencing. We have excluded the possibility that mutations in exon 1 of GJB2 and the deletion of GJB6 are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,Cx26;2975,connexin 31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,1
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (g.27546T>A, c.379T>A, @VARIANT$; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in WNT10A (g.14574G>C, @VARIANT$, p.Glu167Gln) (Figure 4A). The LRP6 c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS. It was predicted to be ""possibly damaging"", with a PolyPhen-2 score of 0.767. The @GENE$ mutation (c.499G>C, rs148714379), while being rare (MAF = 0.0003), was categorized as a benign variant (PolyPhen-2 score = 0.087). Segregation analysis showed that the father carried the two @GENE$ variants, while the mother and the younger sister were both heterozygotes for the WNT10A mutation.",8621929,WNT10A;22525,LRP6;1747,p.Ser127Thr;tmVar:p|SUB|S|127|T;HGVS:p.S127T;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,c.499G>C;tmVar:c|SUB|G|499|C;HGVS:c.499G>C;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"Four potential pathogenic variants, including SCN5A p.R1865H (NM_001160160, c.G5594A), LAMA2 @VARIANT$ (NM_000426, c.G2881A), @GENE$ p.307_308del (NM_001204798, @VARIANT$), and DMD p.E1028V (NM_004011, c.A3083T) were involved in the occurrence of arrhythmia and cardiomyopathy (Table 2). In these known and candidate genes, KCNH2 gene encodes voltage-gated potassium channel activity of cardiomyocytes, which participated in the action potential repolarization. @GENE$ gene encodes for voltage-gated sodium channel subunit as an integral membrane protein, responsible for the initial upstroke of the action potential (obtained from GenBank database).",8739608,KCNH2;201,SCN5A;22738,p.A961T;tmVar:p|SUB|A|961|T;HGVS:p.A961T;VariantGroup:2;CorrespondingGene:3908;RS#:147301872;CA#:3993099,c.921_923del;tmVar:c|DEL|921_923|;HGVS:c.921_923del;VariantGroup:11;CorrespondingGene:6331,0
"In addition, 2 genes presented variants in 3 patients: @GENE$ (patients 6, 7 and 8) and @GENE$ (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant @VARIANT$:p.(Asn294Ser) (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,MAML3;41284,NOTCH1;32049,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,c.881A>G;tmVar:c|SUB|A|881|G;HGVS:c.881A>G;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in  Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, GLI2/3, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for @GENE$, FGF10, GLI2, @GENE$ and EYA1; and RET for PIK3R3 with PTPN11, which also is connected with RIPK4.",6726737,EVC;10949,RIPK4;10772,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in PDGFRB were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"@GENE$ @VARIANT$ induced a regional double helix of the amino acids misfolded and largest hydrophobic domain disorganized, which thus mainly caused LQTS. The @GENE$ @VARIANT$ slightly increased the molecular weight and aliphatic index, but reduced the instability index of Nav1.5 protein property, which potentially induced subsequent sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"The @VARIANT$ nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, S275N) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in @GENE$ (@GENE$), were inherited from unaffected father, while DMXL2 p. Gln1626His variant was inherited from unaffected mother. Proband 17 inherited CHD7 p. Trp1994Gly and CDON p. Val969Ile variants from his unaffected father and mother, respectively. Notably, proband P05 in family 05 harbored a de novo FGFR1 c.1664-2A>C variant. Since the FGFR1 c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (DCC @VARIANT$) and a maternal variant (CCDC88C @VARIANT$).",8152424,DDB1 and CUL4 associated factor 17;80067;1642,DCAF17;65979,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,0
"Tumor analysis of the tumor of one of the digenic carriers and the in vitro MMR activity assay indicated retention of MMR function of MSH6 @VARIANT$ protein. In addition, the genetic marker for MAP-tumors (KRAS @VARIANT$) was absent in this tumor, which points toward retained MUTYH repair activity. The combined inheritance of both genetic variants could still result in impaired repair of oxidative DNA damage. More extensive somatic mutation analysis to assess this was, however, not possible, because of low quality of the DNA sample and the unavailability of additional tumor material.         Next to @GENE$ and @GENE$, CUX1 has been described as a cancer-driving gene.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,c.34G > T;tmVar:c|SUB|G|34|T;HGVS:c.34G>T;VariantGroup:12;CorrespondingGene:3845;RS#:587782084;CA#:13137,0
"A comprehensive epilepsy gene panel, including deletion/duplication analysis, revealed variants of unknown significance in @GENE$ (NM_00156.4, c.79T>C, @VARIANT$), @GENE$ (NM_018328.4, @VARIANT$, p.Leu667Trp), and NRXN1 (NM_004801.4, c.2686C>T, p.Arg896Trp), all of which were inherited.",6371743,GAMT;32089,MBD5;81861,p.Tyr27His;tmVar:p|SUB|Y|27|H;HGVS:p.Y27H;VariantGroup:0;CorrespondingGene:2593;RS#:200833152;CA#:295620,c.2000T>G;tmVar:c|SUB|T|2000|G;HGVS:c.2000T>G;VariantGroup:3;CorrespondingGene:55777;RS#:796052711;CA#:315814,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: SOD1 p.G38R, @GENE$ @VARIANT$, and @GENE$ @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: TARDBP p.G287S was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,ANG;74385,DCTN1;3011,p.P136L;tmVar:p|SUB|P|136|L;HGVS:p.P136L;VariantGroup:7;CorrespondingGene:283;RS#:121909543;CA#:258112,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,1
"None of 2,504 self-declared healthy individuals in TGP has both @GENE$, c.1070A > G (@VARIANT$) and @GENE$, c.1175C > T (@VARIANT$).",5868303,TIA1;20692,SQSTM1;31202,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,p.Pro392Leu;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,1
"21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  @GENE$, 23  @GENE$, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, @VARIANT$) and the CAPN9 (NM_006615: c.55G > T, p.Ala19Ser) variants were classified as VUS.",7689793,EBNA1BP2;4969,TRIP6;37757,p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,p.Glu274Asp;tmVar:p|SUB|E|274|D;HGVS:p.E274D;VariantGroup:22;CorrespondingGene:7205;RS#:76826261;CA#:4394675,0
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"In addition, 2 genes presented variants in 3 patients: @GENE$ (patients 6, 7 and 8) and @GENE$ (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant @VARIANT$:p.(Pro623His) (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,MAML3;41284,NOTCH1;32049,c.1868C>A;tmVar:c|SUB|C|1868|A;HGVS:c.1868C>A;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
We identified a novel variant in the NOD2 gene (c.2857A > G @VARIANT$) and two already described missense variants in the @GENE$ gene (S159G and @VARIANT$). The new @GENE$ missense variant was examined in silico with two online bioinformatics tools to predict the potentially deleterious effects of the mutation.,3975370,IL10RA;1196,NOD2;11156,p.K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,G351R;tmVar:p|SUB|G|351|R;HGVS:p.G351R;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,0
"We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The @GENE$ Q214P and @VARIANT$ alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1).",5953556,CYP1B1;68035,TEK;397,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,G743A;tmVar:c|SUB|G|743|A;HGVS:c.743G>A;VariantGroup:12;CorrespondingGene:7010;RS#:202131936;CA#:5016449,0
"In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel @GENE$ variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry @GENE$ variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients.",6707335,GRN;1577,SQSTM1;31202,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and PRICKLE4 @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (@GENE$ c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in @GENE$ and other PCP-associated genes: 01F552 (FZD6 c.1531C>T and CELSR2 c.3800A>G), 335F07 (FZD6 c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant @VARIANT$).",5887939,CELSR1;7665,FZD;8321;8323,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.10147G>A;tmVar:c|SUB|G|10147|A;HGVS:c.10147G>A;VariantGroup:11;CorrespondingGene:2068;RS#:543855329,0
"The genotypes of @GENE$ (NM_001257180.2: c.1787A>G, @VARIANT$) and @GENE$ (NM_002609.4: @VARIANT$, p.Arg106Pro) for available individuals are shown.",8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Quantification of cells with dilated endoplasmic reticulum (ER) and COPII vesicles associated with Golgi by transmission electron microscopy Genotype of cell line Cells with dilated ER (%) Cells with Golgi-associated vesicles (%) Wt (N = 414) 2 (0.5) 309 (75) SEC23Ac.1200G>C/+ (N = 83) 83 (100***) 9 (11***) SEC23Ac.1200G>C/+ MAN1B1@VARIANT$/+ (N = 190) 190 (100***) 3 (1.6***) SEC23Ac.1200G>C/c.@VARIANT$; MAN1B1c.1000C>T/c.1000C>T (N = 328) 328 (100***) 2 (0.6***)  Increased Intracellular and Secreted Pro-COL1A1 in Fibroblasts with Homozygous Mutations in Both @GENE$ and @GENE$ in the Presence of l-Ascorbic Acid SEC23A is required for normal transport of pro-COL1A1, a major extracellular matrix component of bone.",4853519,SEC23A;4642,MAN1B1;5230,c.1000C>T;tmVar:c|SUB|C|1000|T;HGVS:c.1000C>T;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,1200G>C;tmVar:c|SUB|G|1200|C;HGVS:c.1200G>C;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for @GENE$ c.109C>T. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of @VARIANT$ among vertebrates                TOR2A missense variant A TOR2A nonsynonymous SNV (@VARIANT$ [NM_130459.3], p.Arg190Cys [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,REEP4;11888,BSP+;3644,Arg37;tmVar:p|Allele|R|37;VariantGroup:10;CorrespondingGene:80346;RS#:780399718,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
"            Three rare missense variants (R2034Q, @VARIANT$, and E2003D) of the @GENE$ gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,L2118V;tmVar:p|SUB|L|2118|V;HGVS:p.L2118V;VariantGroup:13;CorrespondingGene:80208;RS#:766851227;CA#:7534152,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"However, when combined with the @GENE$ mutations, it led to a severe phenotype of thirteen missing teeth in the proband. This genetic synergism is also supported by the potential digenic inheritance of LRP6 and @GENE$ mutations in Family 4. The proband, who had LRP6 p.(@VARIANT$), p.(Ser127Thr), and WNT10A p.(@VARIANT$) variants, showed ten missing teeth, while her parents, who passed individual mutant alleles, had no missing teeth but microdontia and dysmorphology of specific teeth.",8621929,LRP6;1747,WNT10A;22525,Asn1075Ser;tmVar:p|SUB|N|1075|S;HGVS:p.N1075S;VariantGroup:8;CorrespondingGene:4040;RS#:202124188,Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the @GENE$ protein.     A previously characterized pathogenic nonsense variant (G1177X) and a rare missense alteration (@VARIANT$) were detected in the ALS2 gene, both in heterozygous form. The @GENE$ protein encoded by the ALS2 gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance.",6707335,CCNF;1335,alsin;23264,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,R1499H;tmVar:p|SUB|R|1499|H;HGVS:p.R1499H;VariantGroup:4;CorrespondingGene:57679;RS#:566436589;CA#:2057559,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin S166N, and pendrin F355L mutations on @GENE$ interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after @GENE$ stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 p.T410M mutations. d Temporal bone computed tomography (CT) scan of the patient with mono-allelic EPHA2 p.T511M and SLC26A4 @VARIANT$ mutations.",7067772,EphA2;20929,ephrin-B2;3019,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,p.T410M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of @GENE$ and WNT10A genes.",3842385,WNT10A;22525,EDA;1896,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To the best of our knowledge, two of the identified variants (@GENE$: c.1183C>A, @VARIANT$; and @GENE$: c.535C>A, @VARIANT$) have not been previously identified.",6338360,FOXC2;21091,PITX2;55454,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous @GENE$ c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-@GENE$ E103D and HA-TEK @VARIANT$, respectively, was significantly diminished. GFP-CYP1B1 R368H also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%). No significant change was observed with HA-TEK G743A with GFP-CYP1B1 @VARIANT$ as compared to WT proteins (Fig. 2). The WT and mutant TEK proteins expressed at similar levels in the cells, indicating that the mutations did not affect the expression or stability of the proteins (Fig. 2). We also tested the potential of the mutant TEK and @GENE$ proteins to associate with wild-type CYP1B1 and TEK, respectively.",5953556,TEK;397,CYP1B1;68035,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,E229 K;tmVar:p|SUB|E|229|K;HGVS:p.E229K;VariantGroup:8;CorrespondingGene:1545;RS#:57865060;CA#:145183,0
"Sequence alterations were detected in the COL6A3 (rs144651558), RYR1 (rs143445685), @GENE$ (@VARIANT$), and @GENE$ (@VARIANT$) genes.",6180278,CAPN3;52,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
Causative heterozygous mutations in @GENE$ (p.N382S/@VARIANT$) and @GENE$ (p.I1176L/@VARIANT$) were identified by whole exome sequencing performed on III-1 and IV-1.,7026993,GFI1;3854,MYO6;56417,c.1145A > G;tmVar:c|SUB|A|1145|G;HGVS:c.1145A>G;VariantGroup:1;CorrespondingGene:2672;RS#:28936381;CA#:119872,c.3526A > C;tmVar:c|SUB|A|3526|C;HGVS:c.3526A>C;VariantGroup:2;CorrespondingGene:4646;RS#:755922465;CA#:141060203,1
"In the present study, we found two variants: the E758K variant in two patients and the @VARIANT$ variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,A579T;tmVar:c|SUB|A|579|T;HGVS:c.579A>T;VariantGroup:8;CorrespondingGene:3798;RS#:760135493,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (@GENE$ c.6362G>A and PRICKLE4 c.730C>G), 2F07 (CELSR1 @VARIANT$ and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and SCRIB c.3979G>A). One patient (f93-80) had a novel PTK7 missense variant (c.655A>G) with a rare CELSR2 missense variant (c.1892C>T). Three patients carried missense variants both in FZD and other PCP-associated genes: 01F552 (FZD6 @VARIANT$ and CELSR2 c.3800A>G), 335F07 (@GENE$ c.544G>A and 2 FAT4 missense variants c.5792A>G; c.10384A>G), and 465F99 (rare FZD1 missense variant c.211C>T and a novel FAT4 missense variant c.10147G>A).",5887939,CELSR1;7665,FZD6;2617,c.8807C>T;tmVar:c|SUB|C|8807|T;HGVS:c.8807C>T;VariantGroup:24;CorrespondingGene:9620;RS#:201509338;CA#:10292625,c.1531C>T;tmVar:c|SUB|C|1531|T;HGVS:c.1531C>T;VariantGroup:29;CorrespondingGene:8323;RS#:151339003;CA#:129147,0
"            Three rare missense variants (@VARIANT$, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,R2034Q;tmVar:p|SUB|R|2034|Q;HGVS:p.R2034Q;VariantGroup:26;CorrespondingGene:80208;RS#:750101301;CA#:7534261,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of @VARIANT$. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of @GENE$, this leads to the substitution of Gly at residue 213 to Ser. Sequence analyses revealed that both mutant alleles were from his mother (Fig. 2D), who had a very mild phenotype of isolated tooth agenesis. His father did not have mutations in either of these genes.     ""S3"" is a 14-year-old girl who had the typical clinical characteristics of HED: sparse hair, 26 missing permanent teeth, hypohidrosis, dry skin, and eczema on her body, but no plantar hyperkeratosis or nail abnormalities (Table 1). The heterozygous p.Arg156Cys (c.466C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 156 to Cys.",3842385,WNT10A;22525,EDA;1896,Arg at residue 153 to Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (@VARIANT$) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"However, none of these signs were evident from metabolic work of the patient with PHKA1 @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of GBE1 D413N and NDUFS8 @VARIANT$ variants remain unknown. It is important to note that these variants changed amino acids that are highly conserved in species from human down to bacteria (data not shown). Because dominant mutations in @GENE$ and @GENE$ are associated with MHS, we evaluated MH diagnostic test results from clinical history of these two subjects.",6072915,RYR1;68069,CACNA1S;37257,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,I126V;tmVar:p|SUB|I|126|V;HGVS:p.I126V;VariantGroup:0;CorrespondingGene:4728;RS#:1267270290,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, @VARIANT$ (A/G heterozygous patient and mother, A/A wild type father) and R351G; (B) in the NOD2 exon 9 sequence, the c.2857 A > G substitution consisted in an amino acid substitution, @VARIANT$ (A/G heterozygous patient and mother, A/A wild-type father). Bioinformatics analysis results. (A) Multiple alignment of the amino acid sequence of @GENE$ protein in seven species showed that this is a conserved region; (B) PolyPhen2 (Polymorphism Phenotyping v.2) analysis predicting the probably damaging impact of the K953E substitution with a score of 0.999.",3975370,IL10RA;1196,NOD2;11156,S159G;tmVar:p|SUB|S|159|G;HGVS:p.S159G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,K953E;tmVar:p|SUB|K|953|E;HGVS:p.K953E;VariantGroup:0;CorrespondingGene:64127;RS#:8178561,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The SLC20A2 c.1787A>G (@VARIANT$) variant detected in our study has been reported to cause brain calcification without clinical manifestations due to @GENE$ dysfunction, which probably results in the accumulation of Pi in affected brain regions (Guo et al., 2019). In addition, the @GENE$ @VARIANT$ (p.Arg106Pro) variant, which may destroy the integrity of the BBB, leading to the transfer of Pi from blood vessels into the brain and further promote the accumulation of Pi in affected brain regions.",8172206,PiT2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (@VARIANT$), SNAI2 (@VARIANT$) and C2orf74 (c.101T>G) genes. Variant in @GENE$ is not segregating with the disease phenotype therefore it was excluded as an underlying cause of WS2 in the family.",7877624,MITF;4892,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"c, d) Sequence chromatograms indicating the wild-type, homozygous affected and heterozygous carrier forms of c) the C to T transition at position c.229 changing the @VARIANT$ of the S100A3 protein (c.229C>T; p.R77C) and d) the c.238-241delATTG (@VARIANT$) in S100A13. Mutation name is based on the full-length @GENE$ (NM_002960) and @GENE$ (NM_001024210) transcripts.",6637284,S100A3;2223,S100A13;7523,arginine residue to cysteine at position 77;tmVar:p|SUB|R|77|C;HGVS:p.R77C;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"Patient P0432 has a @VARIANT$ (p.M1344fsX42) mutation in USH2A and a missense mutation in @GENE$ (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and @GENE$ (c.9921T>G).",3125325,CDH23;11142,USH2A;66151,c.4030_4037delATGGCTGG;tmVar:c|DEL|4030_4037|ATGGCTGG;HGVS:c.4030_4037delATGGCTGG;VariantGroup:216;CorrespondingGene:7399,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous p.Gly213Ser (@VARIANT$) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in @GENE$ (c.607C>T; @VARIANT$) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively.",7877624,TYRO3;4585,SNAI3;8500,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the @VARIANT$ and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between SQSTM1 variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the @GENE$ gene in heterozygous form. This case exemplifies the relevant observation of phenotypic pleiotropy and highlights the complexity of the phenotype-genotype correlation.       Variants in the @GENE$ gene has been previously linked to autosomal dominant hereditary spastic paraparesis (SPG10) and to Charcot-Marie-Tooth disease type 2 (CMT2).",6707335,SIGMAR1;39965,KIF5A;55861,E389Q;tmVar:p|SUB|E|389|Q;HGVS:p.E389Q;VariantGroup:24;CorrespondingGene:8878;RS#:1391182750,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an asparagine into serine substitution in codon 166 (N166S) and for the @VARIANT$ of @GENE$ (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an @VARIANT$ (N166S) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in @GENE$ have been shown to be a cause of dominant X-linked ALS. A previously reported (@VARIANT$,) and a novel variant (Q84H) were found in the UBQLN2 gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,M392V;tmVar:p|SUB|M|392|V;HGVS:p.M392V;VariantGroup:17;CorrespondingGene:29978;RS#:104893941,0
"The @VARIANT$ (c.1045G>A) mutation in exon 9 of @GENE$ and heterozygous p.Arg171Cys (c.511C>T) mutation in exon 3 of @GENE$ were detected. These mutations were not found in his father's genome, but because his mother's DNA sample was unavailable, the origin of the mutant alleles was not clear (Fig. 2F).     All novel mutations that were identified in this study were not found in the normal controls. Protein structure analysis The results of protein structure analyses of WNT10A are shown in Figure 3. R171 and @VARIANT$ are conserved residues through these organisms and located on conserved 2D fragments.",3842385,EDA;1896,WNT10A;22525,p.Ala349Thr;tmVar:p|SUB|A|349|T;HGVS:p.A349T;VariantGroup:2;CorrespondingGene:1896;RS#:132630317;CA#:255657,G213;tmVar:c|Allele|G|213;VariantGroup:4;CorrespondingGene:80326;RS#:147680216,0
"We report digenic variants in SCRIB and @GENE$ associated with NTDs in addition to @GENE$ and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of PTK7 c.1925C > G (@VARIANT$) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,PTK7;43672,SCRIB;44228,p.P642R;tmVar:p|SUB|P|642|R;HGVS:p.P642R;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, @VARIANT$ (two patients), @VARIANT$, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.R268C;tmVar:p|SUB|R|268|C;HGVS:p.R268C;VariantGroup:8;CorrespondingGene:128674;RS#:78861628;CA#:9754278,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated @GENE$ mutation (c.1403 C > T; @VARIANT$) and a novel, potentially pathogenic missense @GENE$ variant (c.1018 C > T; @VARIANT$) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,PTPN11;2122,SOS1;4117,p.T468M;tmVar:p|SUB|T|468|M;HGVS:p.T468M;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,p.P340S;tmVar:p|SUB|P|340|S;HGVS:p.P340S;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,1
"On the other hand, two missense mutations of the EPHA2 gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: c.1229C>A (@VARIANT$), @GENE$: @VARIANT$ (p.T511M) (Fig. 6a, b).",7067772,SLC26A4;20132,EPHA2;20929,p.410T>M;tmVar:p|SUB|T|410|M;HGVS:p.T410M;VariantGroup:9;CorrespondingGene:5172;RS#:111033220;CA#:261403,c.1532C>T;tmVar:c|SUB|C|1532|T;HGVS:c.1532C>T;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,1
"(D, E) A total of 293 T-cells were transfected with Flag-tagged WT or mutant FLNB (p.@VARIANT$, p.A2282T) vector plasmids and myc-tagged WT or mutant TTC26 (p.R297C, @VARIANT$). Then, communoprecipitation assays were conducted. Western blot images are representative of n=3 experiments. AIS, adolescent idiopathic scoliosis; WT, wild type. To investigate the protein-protein interactions, we focused on AIS trios with multiple variants. We found that patients in two AIS trios (trios 22 and 27) carried variants in both the @GENE$ and @GENE$ genes (figure 1).",7279190,FLNB;37480,TTC26;11786,R566L;tmVar:p|SUB|R|566|L;HGVS:p.R566L;VariantGroup:1;CorrespondingGene:2317;RS#:778577280,p.R50C;tmVar:p|SUB|R|50|C;HGVS:p.R50C;VariantGroup:21;CorrespondingGene:79989;RS#:143880653;CA#:4508058,0
"In patient AVM028, one novel heterozygous VUS (@VARIANT$ [p.His736Arg]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2). While TIMP3 blocks VEGF/@GENE$ signalling, @GENE$ modulates differentiation and proliferation of blood vessel endothelial cells downstream of VEGF (figure 3).",6161649,VEGFR2;55639,RASA1;2168,c.2207A>G;tmVar:c|SUB|A|2207|G;HGVS:c.2207A>G;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0
"@GENE$ functions as a coreceptor that enhances VEGF/@GENE$ binding to stimulate VEGF signalling. In this case, both the TGF-beta and VEGF signalling pathways could be affected, potentially causing a more severe downstream effect than would occur with variants in only one of the pathways, with the mutations synergising to lead to BAVM. In patient AVM028, one novel heterozygous VUS (c.2207A>G [@VARIANT$]) in RASA1 inherited from the father and one likely pathogenic de novo novel heterozygous variant (@VARIANT$ [p.Leu104Pro]) in TIMP3 were identified (online supplementary table S2).",6161649,SCUBE2;36383,VEGFR2;55639,p.His736Arg;tmVar:p|SUB|H|736|R;HGVS:p.H736R;VariantGroup:6;CorrespondingGene:5921;RS#:1403332745,c.311T>C;tmVar:c|SUB|T|311|C;HGVS:c.311T>C;VariantGroup:7;CorrespondingGene:5783;RS#:1290872293,0
"Both homozygous and compound heterozygous variants in the @GENE$ gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Moreover, mutations in residues close to @VARIANT$ and A194 identified in the families reported here, namely, M163L, R165W, F191L, and A197S in Cx26 as well as @VARIANT$, S198F and G199R in Cx32, have been reported previously in patients with hearing impairment. Interestingly, mutations identified in patients with the skin disease erythrokeratoderma variabilis (EKV) were located within all the protein domains of the Cx31 gene except for the EC2 and TM4 domains, which are main domains for deafness mutations. This correlation between location of mutations and phenotypes, together with the identification of pathological mutations associated with hearing loss in the same region of the EC2 and TM4 domains in these three connexin genes (Cx26, Cx31, and @GENE$) suggested that the EC2 and TM4 domains are important to the function of the Cx31 protein in the inner ear and plays a vital role in forming connexons in the cells of the inner ear. In the present study, we have shown that the missense N166S and A194T mutations in @GENE$ acts in a recessive manner in three unrelated Chinese patients.",2737700,Cx32;137,GJB3;7338,N166;tmVar:p|Allele|N|166;VariantGroup:0;CorrespondingGene:2707;RS#:121908851,F193C;tmVar:p|SUB|F|193|C;HGVS:p.F193C;VariantGroup:15;CorrespondingGene:2706,0
"KCNH2-@VARIANT$ affects also the synchronization between depolarization and repolarization and so increases the risk of cardiac mortality. Therefore, it is a genetic modifier candidate. Finally, as reported in population studies, @GENE$-p.G38S is associated with heart failure, atrial fibrillation, abnormal cardiac repolarization, and an increased risk of ventricular arrhythmia. Nevertheless, in vitro studies demonstrated that the KCNE1-@VARIANT$ variant causes only a mild reduction of the delayed rectifier K+ currents. Therefore, G38S could be a genetic modifier, but the evidence available does not suggest it has an overt effect on the function of the KCNQ1 and @GENE$ channels.",5578023,KCNE1;3753,KCNH2;201,p.K897T;tmVar:p|SUB|K|897|T;HGVS:p.K897T;VariantGroup:0;CorrespondingGene:3757;RS#:1805123;CA#:7162,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"A PCR amplicon containing @GENE$ exons 2 and 3 was partially sequenced and revealed heterozygosity for an intron 2 polymorphism (@VARIANT$), thereby indicating the presence of two copies of each exon and excluding the possibility of exon deletion as the second mutation in this patient. The screening of other genes related to the hypothalamic-pituitary-gonadal axis, in this patient, revealed an additional heterozygous missense mutation (c.[238C > T];[=]) (@VARIANT$) in the @GENE$ gene.",5527354,GNRHR;350,PROKR2;16368,rs373270328;tmVar:rs373270328;VariantGroup:0;CorrespondingGene:2798;RS#:373270328,p.Arg80Cys;tmVar:p|SUB|R|80|C;HGVS:p.R80C;VariantGroup:4;CorrespondingGene:128674;RS#:774093318;CA#:9754400,1
"Notably, the patients carrying the @VARIANT$ and p.I400V mutations, and three patients carrying the p.V435I mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in KAL1, @GENE$, @GENE$, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROKR2;16368,PROK2;9268,p.T688A;tmVar:p|SUB|T|688|A;HGVS:p.T688A;VariantGroup:0;CorrespondingGene:2260;RS#:876661335,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"Pedigree and segregation of the mutations in @GENE$ and GJB3 The deaf proband is indicated by an arrow. GJB2/GJB3 genotypes are given below the respective pedigrees symbol (a, f and k). Direct sequence analysis showing the 235delC mutation (b and g) and wild type (WT) allele (c and h) of GJB2. Direct sequence analysis showing the @VARIANT$ mutation (l) and wild type (WT) allele (m) of GJB2. Direct sequence analysis showing the @VARIANT$ (N166S) mutation (d) and WT allele (e) of @GENE$. Direct sequence analysis showing the 580G>A (A194T) mutation (i and n) and WT allele (j and o) of GJB3.",2737700,GJB2;2975,GJB3;7338,299-300delAT;tmVar:c|DEL|299_300|AT;HGVS:c.299_300delAT;VariantGroup:2;CorrespondingGene:2706;RS#:111033204,497A>G;tmVar:c|SUB|A|497|G;HGVS:c.497A>G;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the @GENE$ gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, @VARIANT$/@VARIANT$ and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"The @VARIANT$ and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the GRN gene. Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,T338I;tmVar:p|SUB|T|338|I;HGVS:p.T338I;VariantGroup:5;CorrespondingGene:4744;RS#:774252076;CA#:10174087,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,0
"Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the @GENE$ (NM_000179.2: c.3299C > T, @VARIANT$) and @GENE$ (NM_001128425.1: c.536A > G, @VARIANT$) genes, while the other 20 genes could not be clearly linked to cancer predisposition.",7689793,MSH6;149,MUTYH;8156,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,p.Tyr179Cys;tmVar:p|SUB|Y|179|C;HGVS:p.Y179C;VariantGroup:15;CorrespondingGene:4595;RS#:145090475,1
"Variants in all known WS candidate genes (EDN3, EDNRB, @GENE$, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"2.3. Functional Consequences of the @GENE$-p.R583H and @GENE$-p.C108Y Variants To investigate the functional consequences of KCNQ1-@VARIANT$ and KCNH2-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Its numerous domains allow @GENE$ to serve as a frame for multiprotein complexes and regulator of ubiquitinated protein turnover. SQSTM1 mutations have been linked with a spectrum of phenotypes, including Paget disease of bone (PDB), ALS, FTD, and MRV. Hence, SQSTM1 mutations can lead to a multisystem proteinopathy although with incomplete penetrance. A single SQSTM1 mutation (@VARIANT$) has been linked to MRV in one family and an unrelated patient. This patient was subsequently found to carry a coexisting @GENE$ variant (@VARIANT$, p.Asn357Ser) by Evila et al.. Evila et al.'s study reported also an additional sporadic MRV case carrying the same TIA1 variant but a different SQSTM1 mutation (p.Pro392Leu), which is known to cause PDB, ALS, and FTD, but the patient's phenotype was not illustrated.",5868303,SQSTM1;31202,TIA1;20692,c.1165+1G>A;tmVar:c|SUB|G|1165+1|A;HGVS:c.1165+1G>A;VariantGroup:8;CorrespondingGene:8878;RS#:796051870(Expired),c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"The @VARIANT$ variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the @GENE$ gene.",6707335,MATR3;7830,DYNC1H1;1053,P11S;tmVar:p|SUB|P|11|S;HGVS:p.P11S;VariantGroup:6;RS#:995345187,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
"This analysis indicated that the @GENE$ variant @VARIANT$ (rs138172448), which results in a p.Val555Ile change, and the @GENE$ gene variant @VARIANT$ (rs144901249), which results in a p.Thr219Ile change, are both predicted to be damaging.",6180278,CAPN3;52,DES;56469,c.1663G>A;tmVar:c|SUB|G|1663|A;HGVS:c.1663G>A;VariantGroup:2;CorrespondingGene:825;RS#:138172448;CA#:7511461,c.656C>T;tmVar:c|SUB|C|656|T;HGVS:c.656C>T;VariantGroup:3;CorrespondingGene:1674;RS#:144901249;CA#:2125118,0
"Except for the @GENE$ gene variant [p.(Glu436Lys)], mutations identified in DUSP6, ANOS1, DCC, PLXNA1, and PROP1 genes were carried by HH1 family cases (HH1, HH1F, and HH1P) and involved in pathogenic digenic combinations with the @GENE$ gene variant [p.(@VARIANT$)]. Such findings bring into question their involvement in disease expression in HH12. The SEMA7A variant [p.(@VARIANT$)] was predicted as VUS by Varsome.",8446458,SEMA7A;2678,DUSP6;55621,Val114Leu;tmVar:p|SUB|V|114|L;HGVS:p.V114L;VariantGroup:5;CorrespondingGene:1848;RS#:2279574;CA#:6714072,Glu436Lys;tmVar:p|SUB|E|436|K;HGVS:p.E436K;VariantGroup:8;CorrespondingGene:54756;RS#:1411341050,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and @VARIANT$ of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB2;2975,GJB6;4936,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in @GENE$ (NM_001127222.1: @VARIANT$, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: @VARIANT$, p.Arg190Cys), and @GENE$ (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,CACNA1A;56383,ATP2A3;69131,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,c.568C>T;tmVar:c|SUB|C|568|T;HGVS:c.568C>T;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
The proband's father with the @GENE$ c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the @GENE$ @VARIANT$ (p.Arg106Pro) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
"RESULTS Mutations at the gap junction proteins @GENE$ and @GENE$ can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,Cx26;2975,Cx31;7338,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"We found that @GENE$-@VARIANT$ was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and @GENE$-@VARIANT$ could be LQTS modifiers.",5578023,KCNQ1;85014,KCNE1;3753,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = gap junction protein beta 3, @GENE$ = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,GJB6;4936,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"In addition, 2 genes presented variants in 3 patients: @GENE$ (patients 6, 7 and 8) and @GENE$ (patients 1, 4 and 8). Furthermore, RIPK4 presented 2 variants in patient 1. Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ).",6726737,MAML3;41284,NOTCH1;32049,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"However, none of these signs were evident from metabolic work of the patient with PHKA1 @VARIANT$, thus ruling out pathogenic significance of this variant. Pathogenic effects of @GENE$ @VARIANT$ and @GENE$ I126V variants remain unknown.",6072915,GBE1;129,NDUFS8;1867,L718F;tmVar:p|SUB|L|718|F;HGVS:p.L718F;VariantGroup:7;CorrespondingGene:5256;RS#:931442658;CA#:327030635,D413N;tmVar:p|SUB|D|413|N;HGVS:p.D413N;VariantGroup:8;CorrespondingGene:2632;RS#:752711257,0
"18 ,  19  This gene codes for several isoforms, including the ubiquitously expressed p200 CUX1, which, among other functions, has been shown to stimulate the repair of oxidized DNA bases by @GENE$. 20  The identified @GENE$ (NM_001202543: @VARIANT$, p.Ser480Gly) variant, however, was classified as likely benign by the Franklin variant classification tool. 21  Additional gene reportedly linked to tumorigenesis include RYR3, 22  EBNA1BP2, 23  TRIP6, 24  and CAPN9. 25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, p.Asn345Ile) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS.",7689793,OGG1;1909,CUX1;22551,c.1438A > G;tmVar:c|SUB|A|1438|G;HGVS:c.1438A>G;VariantGroup:2;CorrespondingGene:1523;RS#:147066011;CA#:4410849,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) @VARIANT$ (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.317G>C;tmVar:c|SUB|G|317|C;HGVS:c.317G>C;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,0
"(A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The @GENE$ mutation c.936C>G and @GENE$ mutation @VARIANT$ were found in patient N2, who also inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
(b) A sequence chromatogram showing the @GENE$ (c.253C>T;@VARIANT$) mutation. (c) A sequence chromatogram showing the @GENE$ (c.1306A>G;@VARIANT$) mutation.,5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,p.I436V;tmVar:p|SUB|I|436|V;HGVS:p.I436V;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
Merged images showing pro-COL1A1 colocalization with @GENE$ in wild-type (C); SEC23AM400I/+ heterozygous (F); SEC23AM400I/+ @GENE$R334C/+ double heterozygous (I); and SEC23AM400I/@VARIANT$ MAN1B1R334C/@VARIANT$ double-homozygous (L) fibroblasts.,4853519,TGN38;136490,MAN1B1;5230,M400I;tmVar:p|SUB|M|400|I;HGVS:p.M400I;VariantGroup:0;CorrespondingGene:10484;RS#:866845715;CA#:259543384,R334C;tmVar:p|SUB|R|334|C;HGVS:p.R334C;VariantGroup:4;CorrespondingGene:11253;RS#:387906886;CA#:129197,0
"The @VARIANT$ (p.R77C) variant in S100A3 and c.238-241delATTG (@VARIANT$) mutation in S100A13 also segregated fully with ILD in Families 1B and 2.             Haplotype analysis Haplotype analysis carried out using eight markers (four microsatellite markers flanking @GENE$, @GENE$ and three further intragenic markers) (supplementary figure S1a) confirmed that all affected individuals from both families shared a specific disease haplotype on both chromosomes that was not present in the unaffected individuals, suggesting a shared extended haplotype from a common founder.",6637284,S100A3;2223,S100A13;7523,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"Transactivation reporter analyses showed partial functional alteration of three identified amino acid substitutions (FOXC2: @VARIANT$ and @VARIANT$; @GENE$: p.(P179T)). In summary, the increased frequency in PCG patients of rare @GENE$ and PITX2 variants with mild functional alterations, suggests they play a role as putative modifier factors in this disease further supporting that CG is not a simple monogenic disease and provides novel insights into the complex pathological mechanisms that underlie CG.",6338360,PITX2;55454,FOXC2;21091,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(H395N);tmVar:p|SUB|H|395|N;HGVS:p.H395N;VariantGroup:8;CorrespondingGene:2303,0
"Loss-of-function @GENE$ variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the @VARIANT$ in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the SQSTM1 gene were originally reported in Paget's disease of bone. However, recent publications suggest a link between @GENE$ variants and ALS/FTD. The P392L and R393Q variants are known variants reported by other study groups. Interestingly, the patient (#73u) carrying the novel E389Q variant was also diagnosed with Paget's disease of bone. In addition, this patient also carried a variant of unknown significance (@VARIANT$) in the SIGMAR1 gene in heterozygous form.",6707335,GRN;1577,SQSTM1;31202,P392L;tmVar:p|SUB|P|392|L;HGVS:p.P392L;VariantGroup:17;CorrespondingGene:8878;RS#:104893941;CA#:203866,I42R;tmVar:p|SUB|I|42|R;HGVS:p.I42R;VariantGroup:1;CorrespondingGene:10280;RS#:1206984068,0
"Finally, BNC2 variant c.1868C>A:@VARIANT$ (MAF = 0.002) was detected in 2 patients (patient 1 and 7) and MAML3 variant c.881A>G:@VARIANT$ (MAF = 0.0028) in patients 7 and 8 ( Table 2 ). We performed interactome analysis for the identified DSD genes using bioinformatic tools for the analysis of possible gene-protein interactions. The network comprising all genes identified is shown in  Figure 1 . Overall, a connection was found for 27 of the 41 genes. MAMLD1 connects directly to MAML1/2/3. Via NOTCH1/2 8 genes are in connection with MAMLD1, namely WNT9A/9B, @GENE$, FGF10, RET, PROP1 and NRP1. Some of these genes are also central nodes for further connections; e.g. GLI3 for EVC, FGF10, GLI2, RIPK4 and EYA1; and RET for PIK3R3 with PTPN11, which also is connected with @GENE$. RIPK4 itself is a central node for ZBTB16, CUL4B, GLI3 and PTPN11.",6726737,GLI2/3;2736;2737,RIPK4;10772,p.(Pro623His);tmVar:p|SUB|P|623|H;HGVS:p.P623H;VariantGroup:11;CorrespondingGene:54796;RS#:114596065;CA#:204322,p.(Asn294Ser);tmVar:p|SUB|N|294|S;HGVS:p.N294S;VariantGroup:16;CorrespondingGene:55534;RS#:115966590;CA#:3085269,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin @VARIANT$ mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that EphA2 could control both pendrin recruitment to the plasma membrane and @GENE$ exclusion from the plasma membrane.   @GENE$ mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA.",7067772,pendrin;20132,EPHA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the P505L NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and @VARIANT$ in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,R393Q;tmVar:p|SUB|R|393|Q;HGVS:p.R393Q;VariantGroup:15;CorrespondingGene:8878;RS#:200551825;CA#:3600852,0
"Since @VARIANT$ was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous FGFR1 mutation (@VARIANT$), suggesting digenic disease. This NELF deletion was associated with exon 10 skipping, but was not sufficient to cause KS alone. Therefore, no human NELF mutations, supported in vitro, and without mutations in a second gene, have been reported to cause IHH/KS. In the present study, 3/168 (1.8%) of IHH/KS patients had NELF mutations demonstrating impaired function in vitro, which is similar to GNRHR and greater than @GENE$ mutations in nIHH patients. To exclude digenic disease, sequencing of 11 additional genes (CHD7, FGF8, FGFR1, PROK2, PROKR2, @GENE$, TACR3, KAL1, GNRHR, GNRH1, and KISS1R) was performed.",3888818,KISS1R;11411,TAC3;7560,Thr478;tmVar:p|Allele|T|478;VariantGroup:0;CorrespondingGene:26012;RS#:121918340,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0
"  Exome analysis for the proband identified three sequence variants in FTA candidate genes, two in LRP6 (@VARIANT$, c.379T>A, p.Ser127Thr; g.124339A>G, c.3224A>G, p.Asn1075Ser) and one in @GENE$ (g.14574G>C, c.499G>C, @VARIANT$) (Figure 4A). The @GENE$ c.3224A>G mutation is a rare variant with an MAF of 0.0024 in EAS.",8621929,WNT10A;22525,LRP6;1747,g.27546T>A;tmVar:g|SUB|T|27546|A;HGVS:g.27546T>A;VariantGroup:1;CorrespondingGene:4040;RS#:17848270;CA#:6455897,p.Glu167Gln;tmVar:p|SUB|E|167|Q;HGVS:p.E167Q;VariantGroup:5;CorrespondingGene:80326;RS#:148714379,0
"The proband (arrow, II.2) is heterozygous for both the TCF3 T168fsX191 and TNFRSF13B/@GENE$ C104R mutations. Other family members who have inherited @GENE$ @VARIANT$ and TNFRSF13B/TACI @VARIANT$ mutations are shown.",5671988,TACI;49320,TCF3;2408,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and @GENE$ genes.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, p.Met168Arg; g.112084C>G, c.2450C>G, p.Ser817Cys; @VARIANT$, c.4333A>G, p.Met1445Val) and one in @GENE$ (g.14712G>A, @VARIANT$, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,g.146466A>G;tmVar:g|SUB|A|146466|G;HGVS:g.146466A>G;VariantGroup:6;CorrespondingGene:4040;RS#:761703397,c.637G>A;tmVar:c|SUB|G|637|A;HGVS:c.637G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of GJB2 and a monoallelic @VARIANT$ variant of GJB3. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = @GENE$, GJB3 = @GENE$, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,gap junction protein beta 2;2975,gap junction protein beta 3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,MITF;4892,TYRO3;4585,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,1
"Since @GENE$ is an intraflagellar transport (IFT) protein in cilia, we aimed to identify potential interactions between FLNB and TTC26. Using coimmunoprecipitation assays, we found that the myc-tagged mutant p.R50C and p.R197C TTC26 proteins pulled down the Flag-tagged mutant p.A2282T and p.R566L FLNB proteins, respectively (figure 2D, E).   We were also interested in case 98-73, whose twin sister was also diagnosed with AIS (figure 3A). The FLNB missense variant p.R2003H is located in a highly conserved region of the FLNB protein (figure 3B). In silico analyses (figure 3C) indicated that the R2003 residue was solvent accessible and was positioned far from the beta-sheet secondary structure. In the FLNB mutant protein structure, the side-chain of H2003 formed a strong hydrogen bond with E2078. Since OFD1 localises to the base of the cilium, we assumed that FLNB may interact with OFD1. Coimmunoprecipitation analysis indicated an interaction between wild-type @GENE$ and wild-type FLNB, which did not exist between @VARIANT$ FLNB and @VARIANT$ OFD1 (figure 3D).",7279190,TTC26;11786,OFD1;2677,p.R2003H;tmVar:p|SUB|R|2003|H;HGVS:p.R2003H;VariantGroup:18;CorrespondingGene:2317;RS#:563096120;CA#:2469226,p.Y437F;tmVar:p|SUB|Y|437|F;HGVS:p.Y437F;VariantGroup:30;CorrespondingGene:8481,0
"Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (@GENE$) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and @VARIANT$ missense mutation in trans, while case B carried a deletion of @GENE$ exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (@VARIANT$) in TBK1.",4470809,TBK1;22742,OPTN;11085,p.A481V;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB @VARIANT$ and @GENE$ p.R408C with SETX @VARIANT$ and @GENE$ p.T14I).,4293318,TAF15;131088,SETX;41003,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"Deleterious variants in @GENE$ (NM_022460.3: c.94C>A, @VARIANT$) and GNA14 (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in @GENE$,TRPV4,CAPN11,VPS13C,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,HS1BP3;10980,DNAH17;72102,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, @GENE$, SOX10, @GENE$, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,PAX3;22494,SNAI2;31127,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"The @GENE$ and @GENE$ variants were excluded based on their frequencies in normal population cohorts. Sanger sequencing of Family 1 showed that both rs138355706 in S100A3 (@VARIANT$, missense causing a p.R77C mutation) and a 4 bp deletion in S100A13 (c.238-241delATTG causing a frameshift @VARIANT$) segregated completely with ILD in Family 1 based upon recessive inheritance (figure 2c and d), were in total linkage disequilibrium, and were present in a cis conformation.",6637284,ISG20L2;12814,SETDB1;32157,c.229C>T;tmVar:c|SUB|C|229|T;HGVS:c.229C>T;VariantGroup:3;CorrespondingGene:6274;RS#:138355706;CA#:1116284,p.I80Gfs*13;tmVar:p|FS|I|80|G|13;HGVS:p.I80GfsX13;VariantGroup:7;CorrespondingGene:6284,0
"WES demonstrated heterozygous missense mutations in two genes required for pituitary development, a known loss-of-function mutation in PROKR2 (@VARIANT$;p.R85C) inherited from an unaffected mother, and a @GENE$ (@VARIANT$;p.I436V) mutation inherited from an unaffected father. Mutant WDR11 loses its capacity to bind to its functional partner, @GENE$, and to localize to the nucleus.",5505202,WDR11;41229,EMX1;55799,c.253C>T;tmVar:c|SUB|C|253|T;HGVS:c.253C>T;VariantGroup:1;CorrespondingGene:128674;RS#:74315418;CA#:259601,c.1306A>G;tmVar:c|SUB|A|1306|G;HGVS:c.1306A>G;VariantGroup:3;CorrespondingGene:55717;RS#:34602786;CA#:5719694,0
A male (ID104) was found to have a heterozygous missense variant @VARIANT$ (p.Lys330Met) in @GENE$ and a missense variant @VARIANT$ (p.Leu593Val) in @GENE$. Limited clinical information was available about this male.,7463850,EHMT1;11698,SLC9A6;55971,c.989A > T;tmVar:c|SUB|A|989|T;HGVS:c.989A>T;VariantGroup:1;CorrespondingGene:79813;RS#:764291502;CA#:5375151,c.1777C > G;tmVar:c|SUB|C|1777|G;HGVS:c.1777C>G;VariantGroup:7;CorrespondingGene:10479;RS#:149360465,1
"Amino acid conservation analysis showed that seven of the 10 variants (@GENE$ p.G1122S, CELSR1 @VARIANT$, @GENE$ p.R148Q, PTK7 p.P642R, SCRIB @VARIANT$, SCRIB p.G644V and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,CELSR1;7665,DVL3;20928,p.R769W;tmVar:p|SUB|R|769|W;HGVS:p.R769W;VariantGroup:4;CorrespondingGene:9620;RS#:201601181,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"In Family A, there was digenic inheritance of two heterozygous variants: a novel variant in @GENE$ (c.3925G > A, p.Asp1309Asn) and a known DCM mutation in @GENE$ (c.2770G > A; @VARIANT$). The LAMA4 @VARIANT$ variant was predicted to be likely pathogenic according to international guidelines.",6359299,LAMA4;37604,MYH7;68044,p.Glu924Lys;tmVar:p|SUB|E|924|K;HGVS:p.E924K;VariantGroup:0;CorrespondingGene:4625;RS#:121913628;CA#:13034,p.Asp1309Asn;tmVar:p|SUB|D|1309|N;HGVS:p.D1309N;VariantGroup:1;CorrespondingGene:3910;RS#:782046057,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic C to T transition at nucleotide 511 (@VARIANT$) of the coding sequence in exon 3 of WNT10A was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.",3842385,EDA;1896,WNT10A;22525,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Previously, Miura et al demonstrated a heterozygous c.1438A>G (@VARIANT$) @GENE$ variant in 1/65 IHH patients based upon sequence AY_255128 (now revised to c.1432A>G ;p.Thr478Ala from NP_056352). Since Thr478 was only partially conserved (Figure S1B) and no in vitro analysis was performed, its functional significance is unknown. No other IHH/KS genes were studied, so digenic disease cannot be excluded. One heterozygous NELF splice mutation (c.1159-14_22del) has been described. However, the only KS individual within the family also had a heterozygous @GENE$ mutation (@VARIANT$), suggesting digenic disease.",3888818,NELF;10648,FGFR1;69065,p.Thr480Ala;tmVar:p|SUB|T|480|A;HGVS:p.T480A;VariantGroup:0;CorrespondingGene:26012;RS#:121918340;CA#:130174,p.Leu342Ser;tmVar:p|SUB|L|342|S;HGVS:p.L342S;VariantGroup:2;CorrespondingGene:2260;RS#:121909638;CA#:130218,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/N166S, 235delC/@VARIANT$ and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"(A) In the @GENE$ exon 4 and exon 9, the arrows indicate the nucleotide substitution, c.475A > G and c.1051A > G, consisting, respectively, in the amino acid substitutions, S159G (A/G heterozygous patient and mother, A/A wild type father) and @VARIANT$; (B) in the @GENE$ exon 9 sequence, the @VARIANT$ substitution consisted in an amino acid substitution, K953E (A/G heterozygous patient and mother, A/A wild-type father).",3975370,IL10RA;1196,NOD2;11156,R351G;tmVar:p|SUB|R|351|G;HGVS:p.R351G;VariantGroup:0;CorrespondingGene:3587;RS#:8178561,c.2857 A > G;tmVar:c|SUB|A|2857|G;HGVS:c.2857A>G;VariantGroup:0;CorrespondingGene:64127;RS#:8178561;CA#:10006322,1
"In the present study, we found two variants: the @VARIANT$ variant in two patients and the A579T variant in one case, with both variants located within the coiled-coil domain (amino acid positions 331-906) of the protein, which is not in line with previous findings. Without additional functional evidence, the pathogenicity of these variants is uncertain.             Three rare missense variants (R2034Q, L2118V, and E2003D) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (@VARIANT$) were found in the @GENE$ gene.",6707335,SPG11;41614,UBQLN2;81830,E758K;tmVar:p|SUB|E|758|K;HGVS:p.E758K;VariantGroup:23;CorrespondingGene:3798;RS#:140281678;CA#:6653063,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of GJB3, resulting in an @VARIANT$ (N166S) and for the 235delC of GJB2 (Fig. 1b, d).",2737700,Cx31;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,asparagine into serine substitution in codon 166;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (@VARIANT$/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (c.1559G>A/@VARIANT$) that cosegregated with both the AI phenotype and the @GENE$ mutation.,6785452,LAMA3;18279,ENAM;9698,c.588+1delG;tmVar:c|DEL|588+1|G;HGVS:c.588+1delG;VariantGroup:9;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,1
"DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, @GENE$ = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.                     By screening other gap junction genes, another subject (SH175-389) carrying a single heterozygous p.V193E in GJB2 allele harbored a single heterozygous @VARIANT$ mutant allele of GJB3 (NM_001005752) (SH175-389) with known pathogenicity (Figure 4D). This 2-year-old female showed severe autosomal recessive SNHL with a mean hearing threshold of 87.5 dB HL.   Single Heterozygous @GENE$ Mutant Allele with Unknown Contribution to SNHL in Our Cohort (Group III) A 39-year-old female subject (SH94-208) showed the p.T123N variant of GJB2. The pathogenic potential of the @VARIANT$ variant is controversial.",4998745,GJB3;7338,GJB2;2975,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,0
"The proband (arrow, II.2) is heterozygous for both the @GENE$ @VARIANT$ and TNFRSF13B/TACI C104R mutations. Other family members who have inherited TCF3 T168fsX191 and TNFRSF13B/@GENE$ @VARIANT$ mutations are shown.",5671988,TCF3;2408,TACI;49320,T168fsX191;tmVar:p|FS|T|168||191;HGVS:p.T168fsX191;VariantGroup:1;CorrespondingGene:6929,C104R;tmVar:p|SUB|C|104|R;HGVS:p.C104R;VariantGroup:2;CorrespondingGene:23495;RS#:34557412;CA#:117387,0
"Genotyping analysis revealed that the @GENE$/@VARIANT$ was inherited from the unaffected father and the N166S of GJB3 was inherited from the normal hearing mother (Fig. 1a). In families F and K, a heterozygous missense mutation of a @VARIANT$ of @GENE$ that causes A194T, was found in profoundly deaf probands, who were also heterozygous for GJB2/235delC (Fig. 1g, i) and GJB2/299-300delAT (Fig. 1l, n), respectively.",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,G-to-A transition at nucleotide 580;tmVar:c|SUB|G|580|A;HGVS:c.580G>A;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Variant analysis and incidental findings Of the 19 variants identified in this study, four were previously reported as pathogenic disease causing variants: 1) GBE1 R524Ter; 2) @GENE$ G407RfrTer14; 3) NUBPL IVS8DC; 4) @GENE$ @VARIANT$. Two additional variants, p. T4823 M in RYR1 and @VARIANT$ in CACNA1S, were also previously reported in association with Core myopathy and Malignant Hyperthermia Susceptibility (MHS), respectively.",6072915,PCCB;447,OAT;231,"Y299Ter;tmVar:p|SUB|Y|299,ER|T;HGVS:p.Y299,ERT;VariantGroup:10;CorrespondingGene:4942",p. R498L;tmVar:p|SUB|R|498|L;HGVS:p.R498L;VariantGroup:1;CorrespondingGene:779;RS#:150590855;CA#:78268,0
"Two novel variants were identified in @GENE$, including one frameshift mutation (c.2060_2060delG, p.C687LfsX34) and one missense mutation (@VARIANT$, p.G505D). A novel missense mutation was found in DUOXA2 (c.398G>A, p.R133H). Besides 28 rare nonpolymorphic variants, two polymorphic variants in @GENE$, p.H678R and @VARIANT$, were commonly identified with frequencies of 0.19 and 0.286, respectively, which were higher than those in the controls (0.19 versus 0.092, OR (odds ratio) = 2.327, P = 0.097; 0.286 versus 0.085, OR = 4.306, P = 0.001).",6098846,TG;2430,DUOX2;9689,c.1514G>A;tmVar:c|SUB|G|1514|A;HGVS:c.1514G>A;VariantGroup:10;CorrespondingGene:6528;RS#:867829370,p.S1067L;tmVar:p|SUB|S|1067|L;HGVS:p.S1067L;VariantGroup:4;CorrespondingGene:50506;RS#:269868;CA#:7537960,0
"Importantly, one of the TBK1 missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro. The 5 variants with CADD_Phred scores below 20 are less likely to be pathogenic and were located outside the previously reported domains implicated in disease (@GENE$), previously seen in controls (PFN1), or when identified in a family, did not segregate with the disease (@GENE$).       CNV analysis of the 21 neurodegenerative disease genes using Ingenuity Variant Analysis software further identified one patient with a partial deletion of OPTN (NM_001008211.1:@VARIANT$; p.Gly538Glufs27).",4470809,CSF1R;3817,FUS;2521,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,c.1243-740_1612+1292delins25;tmVar:c|INDEL|1243-740_1612+1292|25;HGVS:c.1243-740_1612+1292delins25;VariantGroup:37;CorrespondingGene:10133,0
"Whole genome SNP genotyping, whole exome sequencing followed by Sanger validation of variants of interest identified a novel single nucleotide deletion mutation (@VARIANT$) in the @GENE$ gene. Moreover, a rare heterozygous, missense damaging variant (@VARIANT$; p.Val34Gly) in the C2orf74 has also been identified. The @GENE$ is an uncharacterized gene present in the linked region detected by DominantMapper.",7877624,MITF;4892,C2orf74;49849,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.101T>G;tmVar:c|SUB|T|101|G;HGVS:c.101T>G;VariantGroup:0;CorrespondingGene:339804;RS#:565619614;CA#:1674263,0
"In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (@VARIANT$), @GENE$ (@VARIANT$; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G. The mutations in MYO7A, USH1G and USH2A were not found in 666 control alleles. Of the four siblings, the affected girl is the only one who carries the mutations in @GENE$ and USH1G, and, all the more, the mutations in the three genes (Figure 2).",3125325,USH1G;56113,MYO7A;219,c.6657T>C;tmVar:c|SUB|T|6657|C;HGVS:c.6657T>C;VariantGroup:153;CorrespondingGene:4647,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"Results Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: @VARIANT$, @VARIANT$), @GENE$ (NM_025232.3: c.109C>T, p.Arg37Trp), @GENE$ (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees.",6081235,REEP4;11888,TOR2A;25260,c.7261_7262delinsGT;tmVar:c|INDEL|7261_7262|GT;HGVS:c.7261_7262delinsGT;VariantGroup:32;CorrespondingGene:773,p.Pro2421Val;tmVar:p|SUB|P|2421|V;HGVS:p.P2421V;VariantGroup:3;CorrespondingGene:80346,0
"The p.Ile312Met (c.936C>G) mutation in @GENE$ and heterozygous p.Arg171Cys (@VARIANT$) mutation in @GENE$ were detected. The coding sequence in exon 9 of EDA showed a C to G transition, which results in the substitution of @VARIANT$; also, the coding sequence in exon 3 of WNT10A showed a C to T transition at nucleotide 511, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,Ile at residue 312 to Met;tmVar:p|SUB|I|312|M;HGVS:p.I312M;VariantGroup:7;CorrespondingGene:1896,0
"@GENE$ and DSCAM have similar neurodevelopmental functions and are essential for self-avoidance in the developing mouse retina.     In patient AVM144, the compound heterozygous variants @VARIANT$ and c.1000T>A (@VARIANT$) were identified in @GENE$ (table 2).",6161649,DSCAML1;79549,PTPN13;7909,c.116-1G>A;tmVar:c|SUB|G|116-1|A;HGVS:c.116-1G>A;VariantGroup:5;CorrespondingGene:83394;RS#:1212415588,p.Ser334Thr;tmVar:p|SUB|S|334|T;HGVS:p.S334T;VariantGroup:0;CorrespondingGene:5783;RS#:755467869;CA#:2995566,0
"A single-nucleotide duplication (@VARIANT$/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide @GENE$ deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous @GENE$ mutation (c.1559G>A/@VARIANT$) that cosegregated with both the AI phenotype and the ENAM mutation.",6785452,ENAM;9698,LAMA3;18279,c.395dupA;tmVar:c|DUP|395|A|;HGVS:c.395dupA;VariantGroup:18;CorrespondingGene:13801,p.Cys520Tyr;tmVar:p|SUB|C|520|Y;HGVS:p.C520Y;VariantGroup:6;CorrespondingGene:3909,0
"Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and @GENE$ (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients. Variant in SNAI3 (@VARIANT$; p.Arg203Cys) gene is rare in population and is probably damaging and deleterious as predicted by PolyPhen2 and SIFT, respectively. Variant in TYRO3 (c.1037T>A; @VARIANT$) gene is present in population databases with high frequency (0.22 MAF) and is benign and tolerated as predicted by PolyPhen2 and SIFT, respectively.   Studies have shown that WNT pathway genes including LEF-1 may modulate the WS2 phenotype in WS2 cases with MITF mutation. Therefore, exome data was searched for variants in WNT pathway genes (LEF-1, @GENE$, APC, ZNRF3, LRP4, LRP5, LRP6, ROR1, ROR2, GSK3, CK1, APC, BCL9, and BCL9L) as well.",7877624,TYRO3;4585,RNF43;37742,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"Previous studies suggested that heterozygous variants in the @GENE$ may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, @GENE$, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SOX10;5055,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: NELF/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; p.Cys163del of KAL1) and NELF/@GENE$ (c. 1160-13C>T of @GENE$ and @VARIANT$; @VARIANT$ of TACR3).,3888818,TACR3;824,NELF;10648,c.824G>A;tmVar:c|SUB|G|824|A;HGVS:c.824G>A;VariantGroup:1;CorrespondingGene:26012;RS#:144292455;CA#:144871,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
Protein structure analysis We performed protein structure analysis on the two @GENE$ mutations (p.R171C and @VARIANT$) and two novel @GENE$ mutations (@VARIANT$ and p.I312M) that were identified in this study.,3842385,WNT10A;22525,EDA;1896,p.G213S;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,p.G257R;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous @GENE$ mutations (p.E103D, p.I148T, @VARIANT$, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of CYP1B1 and TEK mutations. The TEK Q214P and G743A alleles were absent in 1024 controls, whereas very low frequencies of heterozygous TEK E103D (0.005) and I148T (0.016) alleles were found in the control population (Table 1). A compound heterozygous TEK mutation (p.E103D and p.E300G) was also observed in 1 family (PCG38). However, the remaining 20 PCG cases harboring a single heterozygous TEK mutation did not carry any additional mutation in the other 35 adult and childhood glaucoma-associated genes (Supplementary Fig. 1; Supplementary Table 1). The co-occurrence of heterozygous TEK and @GENE$ mutations as seen in our PCG cases were not observed in additional sets of POAG, ARS, Aniridia, and Peter's Anomaly patients.",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,0
"We have excluded the possibility that mutations in exon 1 of @GENE$ and the deletion of @GENE$ are the second mutant allele in these Chinese heterozygous probands. Two different GJB3 mutations (N166S and @VARIANT$) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and @VARIANT$/A194T).",2737700,GJB2;2975,GJB6;4936,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"Whole-exome sequencing testing more than 50 genes known to cause myopathy revealed variants in the @GENE$ (@VARIANT$), RYR1 (rs143445685), CAPN3 (rs138172448), and @GENE$ (@VARIANT$) genes.",6180278,COL6A3;37917,DES;56469,rs144651558;tmVar:rs144651558;VariantGroup:6;CorrespondingGene:1293;RS#:144651558,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"Here, we found that pendrin A372V, L445W, @VARIANT$, and G672E did not bind to @GENE$. Given the fact that loss of EphA2 disturbs pendrin apical localization in vivo and cell surface presentation in vitro, the binding of @GENE$ with EphA2 might be critical for pendrin recruitment to the apical membrane in the inner ear and the thyroid. Thus, loss of the ability of pendrin to bind EphA2 may cause delocalization of pendrin from the plasma membrane. Additionally, we examined the binding ability of EphA2 to four membrane located forms of mutated pendrin. None of the mutants had impaired interaction with EphA2. However, @VARIANT$, which is known to have an intact transporter activity and membrane localization in cultured cells, showed compromised endocytosis after ephrin-B2 stimulation.",7067772,EphA2;20929,pendrin;20132,Q446R;tmVar:p|SUB|Q|446|R;HGVS:p.Q446R;VariantGroup:15;CorrespondingGene:5172;RS#:768471577;CA#:4432777,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), @VARIANT$, and p.G687N pathogenic mutations in @GENE$, @GENE$, PROK2, and FGFR1, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,KAL1;55445,PROKR2;16368,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.H70fsX5;tmVar:p|FS|H|70||5;HGVS:p.H70fsX5;VariantGroup:9;CorrespondingGene:60675,0
"Analysis of the proband's exome revealed four potential disease-causing mutations in FTA candidate genes: three heterozygous missense variants in @GENE$ (g.68531T>G, c.503T>G, @VARIANT$; g.112084C>G, c.2450C>G, p.Ser817Cys; g.146466A>G, c.4333A>G, p.Met1445Val) and one in @GENE$ (@VARIANT$, c.637G>A, p.Gly213Ser) (Figure 2A and Figure S2A,B).",8621929,LRP6;1747,WNT10A;22525,p.Met168Arg;tmVar:p|SUB|M|168|R;HGVS:p.M168R;VariantGroup:9;CorrespondingGene:4040,g.14712G>A;tmVar:g|SUB|G|14712|A;HGVS:g.14712G>A;VariantGroup:7;CorrespondingGene:80326;RS#:147680216;CA#:211313,1
"The latter individuals were also carriers of the @GENE$ nonsense mutation @VARIANT$. It should be noted that the mother and her twin sister were heterozygous for one of the @GENE$ missense mutation @VARIANT$ and one ABCC6 nonsense mutation p.R1141X, suggesting digenic inheritance of their cutaneous findings.",2900916,ABCC6;55559,GGCX;639,p.R1141X;tmVar:p|SUB|R|1141|X;HGVS:p.R1141X;VariantGroup:6;CorrespondingGene:368;RS#:72653706;CA#:129115,p.V255M;tmVar:p|SUB|V|255|M;HGVS:p.V255M;VariantGroup:1;CorrespondingGene:2677;RS#:121909683;CA#:214957,0
"Notably, the patients carrying the p.T688A and p.I400V mutations, and three patients carrying the @VARIANT$ mutation also carry, in heterozygous state, p.Y217D, p.R268C (two patients), p.H70fsX5, and @VARIANT$ pathogenic mutations in KAL1, PROKR2, @GENE$, and @GENE$, respectively (Table 1), which further substantiates the digenic/oligogenic mode of inheritance of KS.",3426548,PROK2;9268,FGFR1;69065,p.V435I;tmVar:p|SUB|V|435|I;HGVS:p.V435I;VariantGroup:1;CorrespondingGene:10371;RS#:147436181;CA#:130481,p.G687N;tmVar:p|SUB|G|687|N;HGVS:p.G687N;VariantGroup:7;RS#:727505376(Expired),0
"Genetic evaluation revealed heterozygous variants in the related genes @GENE$ (@VARIANT$, @VARIANT$) and @GENE$ (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures.",6371743,NRXN1;21005,NRXN2;86984,c.2686C>T;tmVar:c|SUB|C|2686|T;HGVS:c.2686C>T;VariantGroup:1;CorrespondingGene:55777;RS#:796052777;CA#:316143,p.Arg896Trp;tmVar:p|SUB|R|896|W;HGVS:p.R896W;VariantGroup:1;CorrespondingGene:9378;RS#:796052777;CA#:316143,0
"A rare variant in @GENE$, c.428C>T; @VARIANT$, was detected in Case 2 and was classified as VUS. Finally, for Case 7 and her father, a previously reported ZFPM2/FOG2 (c.1632G>A; p.Met544Ile) pathogenic missense alteration was identified. No additional variants in other genes associated with testicular development and DSD were identified by our panel in Cases 3, 5 and 6. We were not able to further analyze Case 4 because of a lack of sample availability. 2.3. Transcription Activity and Protein Expression Testing of Novel NR5A1 Variants To study the impact of the three novel missense variants of NR5A1 on transactivation activity of regulated genes, HEK293 cells were co-transfected with WT or mutant NR5A1 expression vectors and three different promoter reporter constructs essential for steroid and sex hormone biosynthesis. All three novel @GENE$ variants had significantly reduced activity on the CYP17A1 reporter compared to WT (Figure 2A). These results were confirmed for the @VARIANT$ and Cys30Ser variants when using the reporters for CYP11A1 and HSD17B3 (Figure 2B,C).",7696449,AMH;68060,NR5A1;3638,p.Thr143Ile;tmVar:p|SUB|T|143|I;HGVS:p.T143I;VariantGroup:3;CorrespondingGene:268;RS#:139265145;CA#:9062862,His24Leu;tmVar:p|SUB|H|24|L;HGVS:p.H24L;VariantGroup:4;CorrespondingGene:6736;RS#:1262320780,0
"We observed that isoproterenol could enhance the activity of LTCC in the HEK293T cells, which may be associated with the evocation of cAMP/protein kinase A pathways by the activation of the endogenous @GENE$ adrenoreceptors. In summary, we investigated an extremely rare large ERS family with a high incidence of nocturnal SCD, in which we found a pathogenic mutation in CACNA1C (@VARIANT$) with loss-of-function. The penetrance was also incomplete, which was modified by a gain-of-functional @GENE$-@VARIANT$ variant and sex.",5426766,beta2;4257,SCN5A;22738,p.Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d). The MFE of SCN5A p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.           RNA secondary structural prediction. (a, b) Compared with wild-type @GENE$, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus led to a reduction of structural stability. (c, d) SCN5A @VARIANT$ showed no significant influence on the RNA structure, and the MFE value of SCN5A p.R1865H mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (@VARIANT$). Her father carries the mutations in @GENE$ and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,c.9921T>G;tmVar:c|SUB|T|9921|G;HGVS:c.9921T>G;VariantGroup:115;CorrespondingGene:7399;RS#:1057519382,0
"One subject tested homozygous for @GENE$ @VARIANT$, but we did not exclude the possibility of a deletion on one allele. The two additional subjects could each be compound heterozygotes comprised of a rare variant (p.C1554G or p.I2547T with 0.3% and 0.5% MAF in population database respectively) and a novel variant (p.R168Q or p.T14I respectively). The subject carrying p.I2547T and p.T14I was also heterozygous for @GENE$ @VARIANT$ which has previously been reported in a subject with SALS.",4293318,SETX;41003,TAF15;131088,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, rs3795737 in @GENE$, @VARIANT$ in SETDB1 and @VARIANT$ in @GENE$, and one novel variant in S100A13, were identified.",6637284,ISG20L2;12814,S100A3;2223,rs143224912;tmVar:rs143224912;VariantGroup:2;CorrespondingGene:9869;RS#:143224912,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"In Family F, the @GENE$/@VARIANT$ was inherited from the unaffected father and the A194T of GJB3 was likely inherited from the normal hearing deceased mother (Fig. 1f). In Family K, genotyping analysis revealed that the father transmitted the @VARIANT$/@GENE$, while the mother is heterozygous for the GJB2/299-300delAT (Fig. 1k).",2737700,GJB2;2975,GJB3;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Moreover, given the complex association of LQTS mutants in the individuals of the family and the potential causative role of each mutation, and also based on in silico analysis and on evidence from previous studies, we focused on the in vitro functional characterization of the @GENE$-@VARIANT$ and KCNH2-p.C108Y variants. 2.3. Functional Consequences of the KCNQ1-p.R583H and KCNH2-p.C108Y Variants To investigate the functional consequences of KCNQ1-p.R583H and @GENE$-@VARIANT$, we performed whole cell patch clamp experiments in transiently transfected CHO-K1 cells.",5578023,KCNQ1;85014,KCNH2;201,p.R583H;tmVar:p|SUB|R|583|H;HGVS:p.R583H;VariantGroup:4;CorrespondingGene:3784;RS#:199473482;CA#:6304,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,0
"Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-@VARIANT$ and COL4A5-@VARIANT$. Mutations in @GENE$ cause classical X-linked Alport Syndrome, while rare mutations in the @GENE$ have been reported in patients with focal segmental glomerulosclerosis.",5954460,COL4A5;133559,LAMA5;4060,p.Pro1243Leu;tmVar:p|SUB|P|1243|L;HGVS:p.P1243L;VariantGroup:2;CorrespondingGene:3911;RS#:756101090;CA#:9942875,p.Asp654Tyr;tmVar:p|SUB|D|654|Y;HGVS:p.D654Y;VariantGroup:4;CorrespondingGene:1287;RS#:1131692060,1
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, @GENE$, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (@VARIANT$; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,PAX3;22494,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,c.1037T>A;tmVar:c|SUB|T|1037|A;HGVS:c.1037T>A;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous @GENE$ mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The EDA mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"In our study, @VARIANT$(p. Arg631*) and c.1267C > T(p. Arg423*) were the two reported variants, while @VARIANT$(p. Ser509fs) and c.1524del A(p. Ser509fs) were the two novel variants, which led to KS with small phallus, cryptorchidism, and obesity. Four kinds of KAl1 gene variants resulted in the termination of protein synthesis, the production of truncated protein, or the activation of nonsense-mediated mRNA degradation, which destroyed the integrity of the protein structure and led to the loss of protein function.         @GENE$ (PROK2) is a protein that plays an important role in the development of olfactory nerve and GnRH neurons and the regulation of physiological rhythm through its receptor PROKR2. Meanwhile, KS patients present with homozygous, compound heterozygous, and heterozygous gene variants in the @GENE$ and PROKR2 genes, which can be passed down through autosomal dominant or oligogenic inheritance.",8796337,Prokineticin-2;9268,PROKR2;16368,c.1897C > T;tmVar:c|SUB|C|1897|T;HGVS:c.1897C>T;VariantGroup:9;CorrespondingGene:2260;RS#:121909642;CA#:130223,c.1525delA;tmVar:c|DEL|1525|A;HGVS:c.1525delA;VariantGroup:13;CorrespondingGene:3730,0
"In AS patient IID27, the two mutations in @GENE$ and @GENE$ were inherited independently, likely indicating an in trans configuration. There is a splicing site mutation @VARIANT$ in COL4A5, inherited from her mother and a missense mutation c.4421C > T (p. (Thr1474Met)) inherited from her father (Figure 1a). In AS patient IID29, in addition to a glycine substitution (p. (@VARIANT$)) in COL4A3 in the heterozygous state, there was another heterozygous nonsense mutation c.5026C > T in COL4A4 genes.",6565573,COL4A5;133559,COL4A4;20071,c.1339 + 3A>T;tmVar:c|SUB|A|1339+3|T;HGVS:c.1339+3A>T;VariantGroup:23;CorrespondingGene:1287,Gly1119Asp;tmVar:p|SUB|G|1119|D;HGVS:p.G1119D;VariantGroup:21;CorrespondingGene:1285;RS#:764480728;CA#:2147204,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and c.488_490delGTT; @VARIANT$ of KAL1) and NELF/@GENE$ (c. 1160-13C>T of NELF and c.824G>A; @VARIANT$ of TACR3).,3888818,NELF;10648,TACR3;824,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,p.Trp275X;tmVar:p|SUB|W|275|X;HGVS:p.W275X;VariantGroup:1;CorrespondingGene:6870;RS#:144292455;CA#:144871,0
"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in MYO7A (@VARIANT$), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in USH2A and a missense mutation in CDH23 (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; p.L16V) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and USH2A without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in @GENE$. The mutations in @GENE$, USH1G and USH2A were not found in 666 control alleles.",3125325,USH1G;56113,MYO7A;219,p.K268R;tmVar:p|SUB|K|268|R;HGVS:p.K268R;VariantGroup:135;CorrespondingGene:4647;RS#:184866544;CA#:182406,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,0
"However, @GENE$ p.R1865H showed no significant influence on the RNA structure (Figure 4c,d). The MFE of SCN5A p.R1865H mutation (-178.70 kcal/mol) was approximately similar to that of the wild type (-178.30 kcal/mol), which probably induced no obvious change in the centroid secondary structure.           RNA secondary structural prediction. (a, b) Compared with wild-type @GENE$, the structure of KCNH2 p.307_308del affected the single-stranded RNA folding, resulting in a false regional double helix. The minimum free energy (MFE) of KCNH2 @VARIANT$ increased, which thus led to a reduction of structural stability. (c, d) SCN5A p.R1865H showed no significant influence on the RNA structure, and the MFE value of SCN5A @VARIANT$ mutation was approximately similar to that of the wild type     Physical and chemical parameter prediction of protein Compared with the amino acids of wild-type KCNH2 (Table 3), KCNH2 p.307_308del showed a decreasing trend in molecular weight and increasing instability.",8739608,SCN5A;22738,KCNH2;201,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; @VARIANT$); a pathogenic new homozygous nucleotide change in BBS7 that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in @GENE$, leading to the change p.(@VARIANT$).",6567512,BBS2;12122,BBS6;10318,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the MATR3 protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (T2583I and @VARIANT$) in the @GENE$ gene.",6707335,ALS2;23264,DYNC1H1;1053,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,G4290R;tmVar:p|SUB|G|4290|R;HGVS:p.G4290R;VariantGroup:27;CorrespondingGene:1778;RS#:748643448;CA#:7354051,0
Mutations of @GENE$ and SCN5A genes are closely related to LQTS. The mutations of KCNH2 @VARIANT$ and @GENE$ @VARIANT$ were found in the proband by WES and validated as positive by Sanger sequencing.,8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T). Neither of these mutations in Cx31 was detected in DNA from 200 unrelated Chinese controls. Direct physical interaction of Cx26 with Cx31 is supported by data showing that Cx26 and Cx31 have overlapping expression patterns in the cochlea. In addition, by coimmunoprecipitation of mouse cochlear membrane proteins, we identified the presence of heteromeric @GENE$/@GENE$ connexons.",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Patient P0418 carries a nonsense mutation in USH2A (p.S5030X) and a missense mutation in MYO7A (p.K268R), but his brother, who is also clinically affected, does not carry the @GENE$ mutation. Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in USH2A and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (c.46C>G; @VARIANT$) and USH2A (c.9921T>G). Her father carries the mutations in MYO7A and @GENE$ without displaying symptoms of the disease, whilst her unaffected mother carries the mutation in USH1G.",3125325,MYO7A;219,USH2A;66151,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,p.L16V;tmVar:p|SUB|L|16|V;HGVS:p.L16V;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"Although our present cohort did not carry homozygous changes in any of the known PCG genes, we reanalyzed our samples that harbored heterozygous mutations in any of these genes along with the @GENE$ mutations. We observed that in 5 PCG cases heterozygous @GENE$ mutations (@VARIANT$, p.E229 K, and p.R368H) co-occurred with heterozygous TEK mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a).",5953556,TEK;397,CYP1B1;68035,p.A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the @GENE$ @VARIANT$ variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (@GENE$) @VARIANT$, and the rest were missense variants.",8152424,CCDC88C;18903,IGSF10;18712,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,0
"Using SIFT and PolyPhen, the c.1777C > G variant in SLC9A6 was predicted to be damaging, but a different variant at the same amino acid, @VARIANT$ (p.Leu593Phe), was found in the ExAC database at a rate of 8.24 x 10-6.    A male (ID041), unrelated to ID104, carried heterozygous missense variants c.1513G > A (@VARIANT$) in @GENE$ and c.353A > G (p.Asn118Ser) in @GENE$. He was seen at 7 years and 10 months and, at that time, was severely developmentally delayed in multiple domains (motor, cognitive, and language).",7463850,EHMT1;11698,MFSD8;115814,c.1777C > T;tmVar:c|SUB|C|1777|T;HGVS:c.1777C>T;VariantGroup:7;CorrespondingGene:10479;RS#:149360465;CA#:10524857,p.Gly505Ser;tmVar:p|SUB|G|505|S;HGVS:p.G505S;VariantGroup:4;CorrespondingGene:79813;RS#:757679895;CA#:5374656,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature @VARIANT$. Additionally, a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.",3842385,WNT10A;22525,EDA;1896,termination at residue 90;tmVar:p|Allele|X|90;VariantGroup:10;CorrespondingGene:1896,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"(C) The sequence of the @VARIANT$ variant is well-conserved from humans to tunicates. (D) SH175-389 harbored a monoallelic p.V193E variant of @GENE$ and a monoallelic @VARIANT$ variant of @GENE$. DFNB1 = nonsyndromic hearing loss and deafness 1, GJB2 = gap junction protein beta 2, GJB3 = gap junction protein beta 3, GJB6 = gap junction protein beta 6, MITF = microphthalmia-associated transcription factor.",4998745,GJB2;2975,GJB3;7338,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,p.A194T;tmVar:p|SUB|A|194|T;HGVS:p.A194T;VariantGroup:18;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Five anencephaly cases carried rare or novel CELSR1 missense variants, three of whom carried additional rare potentially damaging PCP variants: 01F377 (CELSR1 c.6362G>A and @GENE$ @VARIANT$), 2F07 (CELSR1 c.8807C>T and DVL3 c.1622C>T), 618F05 (CELSR1 c.8282C>T and @GENE$ @VARIANT$).",5887939,PRICKLE4;22752,SCRIB;44228,c.730C>G;tmVar:c|SUB|C|730|G;HGVS:c.730C>G;VariantGroup:12;CorrespondingGene:29964;RS#:141478229;CA#:3802865,c.3979G>A;tmVar:c|SUB|G|3979|A;HGVS:c.3979G>A;VariantGroup:31;CorrespondingGene:23513;RS#:201563528;CA#:4918429,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in @GENE$ (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,SNAI3;8500,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,0
"We observed that in 5 PCG cases heterozygous CYP1B1 mutations (p.A115P, p.E229 K, and @VARIANT$) co-occurred with heterozygous @GENE$ mutations (@VARIANT$, p.I148T, p.Q214P, and p.G743A) indicating a potential digenic inheritance (Fig. 1a). None of the normal controls carried both the heterozygous combinations of @GENE$ and TEK mutations.",5953556,TEK;397,CYP1B1;68035,p.R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,p.E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of @GENE$ (NM_007123), R5143C, @VARIANT$, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (USH2A) and @GENE$ (ANK1) identified in SH 94-208).",4998745,USH2A;66151,Ankyrin 1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,C4870F;tmVar:p|SUB|C|4870|F;HGVS:p.C4870F;VariantGroup:24;CorrespondingGene:7399,0
"Most of the identified variants were heterozygous, except for two homozygous @GENE$ mutations (i.e., p.Lys530* and @VARIANT$) detected in two patients. Most variants were included in the databases or reported in previous studies, except for one heterozygous variant in @GENE$ (i.e., @VARIANT$) that was novel.",8446595,DUOX2;9689,TSHR;315,p.Arg1110Gln;tmVar:p|SUB|R|1110|Q;HGVS:p.R1110Q;VariantGroup:5;CorrespondingGene:50506;RS#:368488511;CA#:7537915,p. Ala579Val;tmVar:p|SUB|A|579|V;HGVS:p.A579V;VariantGroup:31;CorrespondingGene:7253,0
"However, it was hard to determine whether the coexisting interactions of @GENE$ @VARIANT$ and SCN5A p.R1865H increased the risk of young and early-onset LQTS, or whether KCNH2 mutation was only associated with LQTS, while SCN5A mutation was only associated with sinoatrial node dysfunction.                                  CONCLUSIONS We firstly identified the novel digenic heterozygous mutations by WES, KCNH2 p.307_308del and @GENE$ @VARIANT$, which resulted in LQTS with repeat syncope, torsades de pointes, ventricular fibrillation, and sinoatrial node dysfunction.",8739608,KCNH2;201,SCN5A;22738,p.307_308del;tmVar:p|DEL|307_308|;HGVS:p.307_308del;VariantGroup:16;CorrespondingGene:3757,p.R1865H;tmVar:p|SUB|R|1865|H;HGVS:p.R1865H;VariantGroup:1;CorrespondingGene:6331;RS#:370694515;CA#:64651,0
"The nucleotide sequence showed a @VARIANT$ (c.252DelT) of the coding sequence in exon 1 of EDA; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of @VARIANT$. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (c.457C>T) mutation was found in exon 3 of @GENE$, it results in the substitution of Arg at residue 153 to Cys.",3842385,WNT10A;22525,EDA;1896,T deletion at nucleotide 252;tmVar:c|Allele|T|252;VariantGroup:9;CorrespondingGene:1896,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"          Aberrant regulation of pathogenic forms of pendrin via EphA2 Some pathogenic variants of pendrin are not affected by EphA2/@GENE$ regulation. a, b Immunoprecipitation of EphA2 with mutated pendrin. myc-pendrin A372V, @VARIANT$, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-pendrin @VARIANT$, S166N and F355L was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin S166N was not internalized after ephrin-B2 stimulation while EphA2 and other mutated pendrins were not affected. f Relative amount of cell surface @GENE$ is shown.",7067772,ephrin-B2;3019,pendrin;20132,L445W;tmVar:p|SUB|L|445|W;HGVS:p.L445W;VariantGroup:0;CorrespondingGene:5172;RS#:111033307;CA#:253309,L117F;tmVar:p|SUB|L|117|F;HGVS:p.L117F;VariantGroup:18;CorrespondingGene:23985,0
"Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, @VARIANT$) and @GENE$ (NM_004297.3: @VARIANT$, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17,TRPV4,CAPN11,@GENE$,UNC13B,SPTBN4,MYOD1, and MRPL15 were found in two or more independent pedigrees.",6081235,GNA14;68386,VPS13C;41188,p.Gly32Cys;tmVar:p|SUB|G|32|C;HGVS:p.G32C;VariantGroup:25;CorrespondingGene:64342,c.989_990del;tmVar:c|DEL|989_990|;HGVS:c.989_990del;VariantGroup:16;CorrespondingGene:9630;RS#:750424668;CA#:5094137,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"Patient P0418 carries a nonsense mutation in USH2A (@VARIANT$) and a missense mutation in @GENE$ (p.K268R), but his brother, who is also clinically affected, does not carry the MYO7A mutation. Patient P0432 has a c.4030_4037delATGGCTGG (p.M1344fsX42) mutation in @GENE$ and a missense mutation in CDH23 (p.R1189W), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23. In the USH1 patient, we found three presumably pathogenic mutations in MYO7A (c.6657T>C), USH1G (@VARIANT$; p.L16V) and USH2A (c.9921T>G).",3125325,MYO7A;219,USH2A;66151,p.S5030X;tmVar:p|SUB|S|5030|X;HGVS:p.S5030X;VariantGroup:47;CorrespondingGene:7399;RS#:758660532;CA#:1392795,c.46C>G;tmVar:c|SUB|C|46|G;HGVS:c.46C>G;VariantGroup:18;CorrespondingGene:124590;RS#:876657419;CA#:10576353,0
"The pathogenic potential of the @VARIANT$ variant is controversial. Three variants of USH2A (NM_007123), @VARIANT$, C4870F, and G805A with unknown pathogenic potential were identified using TES (see Table S3, Supplemental Content, which illustrates variants or mutations of Usher syndrome type 2A (@GENE$) and Ankyrin 1 (@GENE$) identified in SH 94-208).",4998745,USH2A;66151,ANK1;55427,p.T123N;tmVar:p|SUB|T|123|N;HGVS:p.T123N;VariantGroup:5;CorrespondingGene:2706;RS#:111033188;CA#:134964,R5143C;tmVar:p|SUB|R|5143|C;HGVS:p.R5143C;VariantGroup:6;CorrespondingGene:7399;RS#:145771342;CA#:182576,0
"The detected @VARIANT$ variant affects the nuclear localization signal 2 (amino acids 568-574) of the CCNF protein.     A previously characterized pathogenic nonsense variant (@VARIANT$) and a rare missense alteration (R1499H) were detected in the ALS2 gene, both in heterozygous form. The alsin protein encoded by the @GENE$ gene is involved in endosome/membrane trafficking and fusion, cytoskeletal organization, and neuronal development/maintenance. Both homozygous and compound heterozygous variants in the ALS2 gene have been described as causative for juvenile ALS. The G1177X nonsense variant was first detected in compound heterozygous form in a family with two affected siblings suffering from infantile ascending spastic paralysis with bulbar involvement. The ages of onset of the patients with the ALS2 variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  @GENE$ encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA.",6707335,ALS2;23264,MATR3;7830,R572W;tmVar:p|SUB|R|572|W;HGVS:p.R572W;VariantGroup:25;CorrespondingGene:899;RS#:199743115;CA#:7842683,G1177X;tmVar:p|SUB|G|1177|X;HGVS:p.G1177X;VariantGroup:0;CorrespondingGene:57679;RS#:386134180;CA#:356568,0
"To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in @GENE$ by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (@VARIANT$ and A194T) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,1
The siblings we describe with the HNF1A P291fsinsC and @GENE$ @VARIANT$ mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic. The @GENE$ P291fsinsC (@VARIANT$) mutation is the most common of all MODY mutations: it results in a frameshift and premature termination codon.,4090307,HNF4A;395,HNF1A;459,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,c.872dup;tmVar:c|DUP|872||;HGVS:c.872dup;VariantGroup:1;CorrespondingGene:6927;RS#:587776825,0
"Results Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in @GENE$ (@VARIANT$, p.Pro392Leu) and a heterozygous variant in @GENE$ (@VARIANT$, p.Asn357Ser).",5868303,SQSTM1;31202,TIA1;20692,c.1175C>T;tmVar:c|SUB|C|1175|T;HGVS:c.1175C>T;VariantGroup:1;CorrespondingGene:8878;RS#:104893941;CA#:203866,c.1070A>G;tmVar:c|SUB|A|1070|G;HGVS:c.1070A>G;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,1
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, @GENE$, and LQT6 genes identified a heterozygous c.3092_3096dup (p.Arg1033ValfsX26) mutation of the @GENE$ gene (LQT2) and a heterozygous @VARIANT$ (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6).",6610752,LQT5;71688,KCNH2;201,c.170T > C;tmVar:c|SUB|T|170|C;HGVS:c.170T>C;VariantGroup:0;CorrespondingGene:3757;RS#:794728493;CA#:5221,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"25  The RYR3 (NM_001036: c.7812C > G, p.Asn2604Lys) and EBNA1BP2 (NM_001159936: c.1034A > T, @VARIANT$) variants were classified as likely benign and benign, respectively, while the TRIP6 (NM_003302: c.822G > C, p.Glu274Asp) and the CAPN9 (NM_006615: @VARIANT$, p.Ala19Ser) variants were classified as VUS. 21  TRIP6 promotes cell migration and invasion through Wnt/beta-catenin signaling and was shown to be upregulated in colorectal tumors. 24  Therefore, @GENE$ variants that increase protein stability or expression could potentially stimulate colorectal tumorigenesis. In addition, lost-of-function variants in CAPN9 might promote tumor formation, as Calpain-9 induces cell cycle arrest and apoptosis, and low expression predicts a poorer prognosis in gastric cancer patients. 25  The contribution of the genetic variants, other than MSH6 and @GENE$, to cancer risk cannot be completely excluded.",7689793,TRIP6;37757,MUTYH;8156,p.Asn345Ile;tmVar:p|SUB|N|345|I;HGVS:p.N345I;VariantGroup:5;CorrespondingGene:10969;RS#:11559312;CA#:803919,c.55G > T;tmVar:c|SUB|G|55|T;HGVS:c.55G>T;VariantGroup:17;CorrespondingGene:10753;RS#:147360179;CA#:1448452,0
"Cases A and B carried nonsense mutations in @GENE$ (NM_001008211.1:c.703C>T; p.Gln235*), and TBK1 (NM_013254.3:c.349C>T; @VARIANT$) respectively; while the other 3 TBK1 mutations observed in cases C-E were missense changes. Importantly, one of the @GENE$ missense changes (NM_013254.3:c.2086G>A; @VARIANT$; case C) was recently reported in two Swedish ALS patients and was shown to impair the binding of TBK1 to OPTN in vitro.",4470809,OPTN;11085,TBK1;22742,p.Arg117*;tmVar:p|SUB|R|117|*;HGVS:p.R117*;VariantGroup:12;CorrespondingGene:5216;RS#:140547520,p.Glu696Lys;tmVar:p|SUB|E|696|K;HGVS:p.E696K;VariantGroup:6;CorrespondingGene:29110;RS#:748112833;CA#:203889,0
"Under the assumption of an autosomal recessive inheritance pattern, two variants were identified in @GENE$ (c.326_327insT, p.(Lys111Glnfs*27) and @VARIANT$, p.(Gln2373*)) (Table 1, S3 Fig.). Segregation analysis showed that they were both present on the maternal allele (Figs. 1C-D). By analyzing for the presence of variants in genes implicated in intellectual disability, hearing impairment and inherited retinal disease, a heterozygous stop mutation in @GENE$ (@VARIANT$, p.(Ser512*)), a gene previously shown to be involved in autosomal recessive RP.",5967407,RP1L1;105870,C2orf71;19792,c.7117C>T;tmVar:c|SUB|C|7117|T;HGVS:c.7117C>T;VariantGroup:3;CorrespondingGene:94137;RS#:759654067;CA#:4623074,c.1535C>A;tmVar:c|SUB|C|1535|A;HGVS:c.1535C>A;VariantGroup:1;CorrespondingGene:388939;RS#:1293811678,1
"The nucleotide sequence showed a G to C transition at nucleotide 769 (c.769G>C) of the coding sequence in exon 7 of EDA, which results in the substitution of @VARIANT$. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of @VARIANT$. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,Gly at residue 257 to Arg;tmVar:p|SUB|G|257|R;HGVS:p.G257R;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,Arg at residue 171 to Cys;tmVar:p|SUB|R|171|C;HGVS:p.R171C;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
Two unrelated KS patients had heterozygous NELF mutations and mutation in a second gene: @GENE$/KAL1 (c.757G>A; p.Ala253Thr of NELF and @VARIANT$; @VARIANT$ of @GENE$) and NELF/TACR3 (c. 1160-13C>T of NELF and c.824G>A; p.Trp275X of TACR3).,3888818,NELF;10648,KAL1;55445,c.488_490delGTT;tmVar:p|DEL|488_490|V;HGVS:p.488_490delV;VariantGroup:8;CorrespondingGene:26012,p.Cys163del;tmVar:p|DEL|163|C;HGVS:p.163delC;VariantGroup:10;CorrespondingGene:3730,0
"We provide evidence that mutations in the @GENE$ and @GENE$ genes can interact to cause hearing loss in digenic heterozygotes. RESULTS Mutations at the gap junction proteins Cx26 and Cx31 can interact to cause non-syndromic deafness In total, 108 probands screened for mutations in the Cx26 gene were found to carry a single recessive mutant allele. In those samples, no mutation was detected on the second allele either in Cx26-exon-1/splice sites or in GJB6. To investigate the role of GJB3 variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (@VARIANT$/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,Cx26;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,1
"No mutations in SLC5A5, @GENE$, or @GENE$ gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: c.2779A>G (@VARIANT$) in one patient, (2) DUOX2:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: c.413dupA (@VARIANT$) in one patient.",6098846,TPO;461,IYD;12352,p.M927V;tmVar:p|SUB|M|927|V;HGVS:p.M927V;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,p.Y138X;tmVar:p|SUB|Y|138|X;HGVS:p.Y138X;VariantGroup:14;CorrespondingGene:405753;RS#:778410503;CA#:7539391,0
"All @GENE$ variants tested show a significant decrease in trans-activational activity with SOX9 and with @GENE$. Complete loss of trans-activational activity was noted for the proteins with missense mutations located in the LBD (@VARIANT$ and p.D364Y), the p.47_54 in-frame deletion, as well as both frame-shift mutations assayed (p.R89Gfs*17 and p.L209Cfs*87). The nonsense mutation SF1 (@VARIANT$;Y211*]) seemed to retain a low level of activity.",5765430,SF1;138518,SRY;48168,p.H310D;tmVar:p|SUB|H|310|D;HGVS:p.H310D;VariantGroup:4;CorrespondingGene:6662;RS#:780987236;CA#:8739053,p.[P210Q;tmVar:p|SUB|P|210|Q;HGVS:p.P210Q;VariantGroup:5;CorrespondingGene:2626;RS#:575307727;CA#:4630899,0
"Detection of mutations in @GENE$ and @GENE$ in group I are relatively common in East Asian populations, including Koreans, indicating that application of panel sequencing covering the genes prioritized based on the ethnicity-specific prevalence would be effective for identifying GJB2 single heterozygotes with severe to profound SNHL in Koreans. For the family SH60 with a most likely genetic etiology but without a clear result after TES, whole exome sequencing can be used for definitive molecular diagnosis. This family SH60 segregates prelingual or perilingual severe to profound SNHL, likely in an autosomal dominant fashion, although prelingual SNHL of SH60-136 was caused by autosomal recessive mutations in other deafness genes (Figure 3). Further segregation analyses of the two variants (@VARIANT$ and p.D771N) among the six family members of SH60 as well as clinical evaluations including audiograms excluded both p.R143W of GJB2 and @VARIANT$ of WFS1 as a molecular etiology of SH60-136.",4998745,MYO15A;56504,TMC1;23670,p.R143W;tmVar:p|SUB|R|143|W;HGVS:p.R143W;VariantGroup:1;CorrespondingGene:2706;RS#:80338948;CA#:172234,p.D771N;tmVar:p|SUB|D|771|N;HGVS:p.D771N;VariantGroup:13;CorrespondingGene:7466;RS#:534067035;CA#:2839681,0
"Analyses of his parents' genome showed that the mutant @GENE$ allele was from his mother (Fig. 2C), however, we were unable to screen for @GENE$ mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The @VARIANT$ (c.457C>T) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,p.Arg153Cys;tmVar:p|SUB|R|153|C;HGVS:p.R153C;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
"The results showed that the two @GENE$ variants p.(H395N) and @VARIANT$ were associated with a 22%-28% reduced transactivation (Fig 5A). Only one of the two identified @GENE$ variants, @VARIANT$, could be cloned for functional evaluation.",6338360,FOXC2;21091,PITX2;55454,p.(C498R);tmVar:p|SUB|C|498|R;HGVS:p.C498R;VariantGroup:1;CorrespondingGene:103752587;RS#:61753346;CA#:8218498,p.(P179T);tmVar:p|SUB|P|179|T;HGVS:p.P179T;VariantGroup:3;CorrespondingGene:1545;RS#:771076928,0
"However, proband P05 also carried a paternal variant (@GENE$ @VARIANT$) and a maternal variant (@GENE$ p. Arg1299Cys). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) @VARIANT$, and the rest were missense variants.",8152424,DCC;21081,CCDC88C;18903,p. Gln91Arg;tmVar:p|SUB|Q|91|R;HGVS:p.Q91R;VariantGroup:1;CorrespondingGene:80067;RS#:766366919,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,0
"Therefore, @GENE$ genotyping has not yet entered into clinical practice. On the basis of the data collected in this study, we may speculate that the presence of @GENE$-@VARIANT$, together with three KCNE1-@VARIANT$ alleles, could lead to an increased risk of developing cardiac arrhythmias due to the prolongation of the QT interval.",5578023,NOS1AP;136252,KCNH2;201,p.C108Y;tmVar:p|SUB|C|108|Y;HGVS:p.C108Y;VariantGroup:3;CorrespondingGene:3757,p.G38S;tmVar:p|SUB|G|38|S;HGVS:p.G38S;VariantGroup:1;CorrespondingGene:3753;RS#:1805127;CA#:131330,0
"The hot spot variant c.533G > C (@VARIANT$) was found in six patients and located in the transmembrane domain of the protein, which could significantly reduce the release of ionized calcium and the signal activity.                             The FGFR1 gene is expressed in many tissues and plays an important role in the development of embryonic olfactory nerve and GnRH neurons mainly through the @GENE$/FGFR1 signalling pathway. FGFR1 signalling is essential for the migration, secretion, or survival of hypothalamic GnRH neurons and is widely expressed in the nervous and skeletal systems. The FGFR1 gene is inherited through an autosomal dominant mode. Loss of function can lead to both nIHH and KS, and more than 200 variants of the @GENE$ gene have been found in patients with IHH. The FGFR1 gene had the highest variant frequency, approximately 44% in our study, which was higher than that (10%) in the Caucasian population. Its variant can cause cleft lip and palate, short stature, and bone dysplasia. Among the 11 FGFR1 variants reported in our study, c.761G > A (p. Arg254Gln), @VARIANT$ (p. Arg78Cys), and c.2008G > A (p. Glu670Lys) were found to be pathogenic variants.",8796337,FGF;8822;8822,FGFR1;69065,p. Trp178Ser;tmVar:p|SUB|W|178|S;HGVS:p.W178S;VariantGroup:12;CorrespondingGene:128674;RS#:201835496;CA#:270917,c.232C > T;tmVar:c|SUB|C|232|T;HGVS:c.232C>T;VariantGroup:10;CorrespondingGene:2260,0
"Variants in all known WS candidate genes (@GENE$, @GENE$, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,EDN3;88,EDNRB;89,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of @GENE$ were identified in three unrelated families (@VARIANT$/N166S, 235delC/A194T and 299delAT/@VARIANT$). Neither of these mutations in @GENE$ was detected in DNA from 200 unrelated Chinese controls.",2737700,GJB2;2975,Cx31;7338,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"To investigate the role of GJB3 variations along with @GENE$ mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the @GENE$ gene revealed the presence of two different missense mutations (N166S and @VARIANT$) occurring in compound heterozygosity along with the @VARIANT$ and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T).",2737700,GJB2;2975,Cx31;7338,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these @GENE$ variants are unlikely to be deleterious. Variants in the SPG11 gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"Interestingly, one FALS proband carried 3 variants, each of which has previously been reported as pathogenic: @GENE$ p.G38R, ANG p.P136L, and DCTN1 @VARIANT$. Nine apparently sporadic subjects had variants in multiple genes (Table 4), but only two were well-established ALS mutations: @GENE$ @VARIANT$ was found in combination with VAPB p.M170I while a subject with juvenile-onset ALS carried a de novo FUS p.P525L mutation with a paternally-inherited intermediate-sized CAG expansion in ATXN2.",4293318,SOD1;392,TARDBP;7221,p.T1249I;tmVar:p|SUB|T|1249|I;HGVS:p.T1249I;VariantGroup:53;CorrespondingGene:1639;RS#:72466496;CA#:119583,p.G287S;tmVar:p|SUB|G|287|S;HGVS:p.G287S;VariantGroup:0;CorrespondingGene:23435;RS#:80356719;CA#:586459,0
"So, it is impossible to detect a mutation in a region which is not covered using this system (Case #9: @VARIANT$). Secondarily, the MPS system used in this study, is not effective for detecting homo-polymer regions, for example poly C stretch (Case #8: @VARIANT$). In addition, concerning pathogenecity of mutations identified, functional analysis will be necessary to draw the final conclusion in the future. In UK and US Caucasian USH1 patients, @GENE$ (MYO7A) has been reported as the most common USH1 genetic subtype, while @GENE$ (PCDH15) has been reported as the most common USH1 genetic subtype in North American Ashkenazi Jews.",3949687,USH1B;219,USH1F;23401,c.5821-2A>G;tmVar:c|SUB|A|5821-2|G;HGVS:c.5821-2A>G;VariantGroup:42;CorrespondingGene:64072,p.Lys542GlnfsX5;tmVar:p|FS|K|542|Q|5;HGVS:p.K542QfsX5;VariantGroup:6;CorrespondingGene:4647;RS#:782077721;CA#:6197531,0
"In this study, we sequenced complete exome in two affected individuals and identified candidate variants in @GENE$ (@VARIANT$), @GENE$ (@VARIANT$) and C2orf74 (c.101T>G) genes.",7877624,MITF;4892,SNAI2;31127,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,1
"Twenty-two rare variants were shared by the three patients (Tables 1 and S1), including variants in the MSH6 (NM_000179.2: c.3299C > T, p.Thr1100Met) and @GENE$ (NM_001128425.1: @VARIANT$, p.Tyr179Cys) genes, while the other 20 genes could not be clearly linked to cancer predisposition. The identified @GENE$ variant was classified as a variant of uncertain significance (VUS) in the Leiden Open Variant Database and the InSiGHT DNA Variant Database. 14 ,  15 The MUTYH variant is the most common pathogenic variant found in the Netherlands. 2                       The digenic inheritance of MSH6 and MUTYH variants. A, The pedigree shows the coinheritance of the monoallelic variants which encode MSH6 @VARIANT$ and MUTYH p.Tyr179Cys in a family affected by colorectal cancer.",7689793,MUTYH;8156,MSH6;149,c.536A > G;tmVar:c|SUB|A|536|G;HGVS:c.536A>G;VariantGroup:15;CorrespondingGene:4595;RS#:145090475;CA#:7607273,p.Thr1100Met;tmVar:p|SUB|T|1100|M;HGVS:p.T1100M;VariantGroup:4;CorrespondingGene:2956;RS#:63750442;CA#:12473,0
"(A) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N1, who inherited the mutant allele from his mother. (B) The EDA mutation @VARIANT$ and WNT10A mutation c.511C>T were found in patient N2, who also inherited the mutant allele from his mother. (C) The EDA mutation c.252DelT and WNT10A mutation c.511C>T were found in patient S1, who inherited the mutant EDA allele from his mother; WNT10A mutations in the parents could not be analyzed. (D) The @GENE$ mutation c.457C>T and @GENE$ mutation c.637G>A were found in patient S2, who also inherited the mutant allele from his mother; however, his father's DNA sample could not be obtained for analysis.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.936C>G;tmVar:c|SUB|C|936|G;HGVS:c.936C>G;VariantGroup:1;CorrespondingGene:80326,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 A115P and GFP-CYP1B1 E229K to immunoprecipitate HA-TEK E103D and HA-@GENE$ @VARIANT$, respectively, was significantly diminished. GFP-@GENE$ @VARIANT$ also exhibited relatively reduced ability to immunoprecipitate HA-TEK I148T (~70%).",5953556,TEK;397,CYP1B1;68035,Q214P;tmVar:p|SUB|Q|214|P;HGVS:p.Q214P;VariantGroup:10;CorrespondingGene:7010,R368H;tmVar:p|SUB|R|368|H;HGVS:p.R368H;VariantGroup:1;CorrespondingGene:1545;RS#:79204362;CA#:119016,0
"After filtering for homozygous nonsynonymous single nucleotide variants (SNVs) within the linkage interval, that were either novel or had either low or unknown minor allele frequency in dbSNP, only three previously described variants, @VARIANT$ in ISG20L2, rs143224912 in @GENE$ and @VARIANT$ in @GENE$, and one novel variant in S100A13, were identified.",6637284,SETDB1;32157,S100A3;2223,rs3795737;tmVar:rs3795737;VariantGroup:5;CorrespondingGene:81875;RS#:3795737,rs138355706;tmVar:rs138355706;VariantGroup:3;CorrespondingGene:6274;RS#:138355706,0
"myc-pendrin @VARIANT$, L445W, Q446R, G672E were not co-immunoprecipitated with EphA2. Densitometric quantifications are shown (b). Mean +- SEM; one-way ANOVA with Bonferroni post hoc analyses; *p < 0.05; (n = 3). c, d Immunoprecipitation of EphA2 with mutated pendrin. Immunocomplex of myc-@GENE$ L117F, S166N and @VARIANT$ was not affected. Densitometric quantifications are shown (d). Mean +- SEM; (n = 3). e, f Internalization of EphA2 and mutated pendrin triggered by ephrin-B2 stimulation. Pendrin S166N was not internalized after ephrin-B2 stimulation while @GENE$ and other mutated pendrins were not affected.",7067772,pendrin;20132,EphA2;20929,A372V;tmVar:p|SUB|A|372|V;HGVS:p.A372V;VariantGroup:11;CorrespondingGene:5172;RS#:121908364;CA#:253306,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and @GENE$ and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated PTPN11 mutation (@VARIANT$; p.T468M) and a novel, potentially pathogenic missense @GENE$ variant (@VARIANT$; p.P340S) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position.",5101836,neurofibromatosis 1;226,SOS1;4117,c.1403 C > T;tmVar:c|SUB|C|1403|T;HGVS:c.1403C>T;VariantGroup:6;CorrespondingGene:5781;RS#:121918457;CA#:220134,c.1018 C > T;tmVar:c|SUB|C|1018|T;HGVS:c.1018C>T;VariantGroup:2;CorrespondingGene:6654;RS#:190222208;CA#:1624660,0
"We report digenic variants in SCRIB and PTK7 associated with NTDs in addition to @GENE$ and CELSR1 heterozygous variants in additional NTD cases. The combinatorial variation of @GENE$ @VARIANT$ (p.P642R) and SCRIB c.3323G > A (@VARIANT$) only occurred in one spina bifida case, and was not found in the 1000G database or parental samples of NTD cases.",5966321,SCRIB;44228,PTK7;43672,c.1925C > G;tmVar:c|SUB|C|1925|G;HGVS:c.1925C>G;VariantGroup:5;CorrespondingGene:5754;RS#:148120569;CA#:3816292,p.G1108E;tmVar:p|SUB|G|1108|E;HGVS:p.G1108E;VariantGroup:3;CorrespondingGene:23513;RS#:529610993;CA#:4918763,0
"Amino acid conservation analysis showed that seven of the 10 variants (CELSR1 p.G1122S, CELSR1 p.R769W, DVL3 @VARIANT$, @GENE$ p.P642R, SCRIB p.G1108E, @GENE$ @VARIANT$ and SCRIB p.K618R) were located at highly conserved nucleotides in human, dog, mouse, rat, and zebrafish.",5966321,PTK7;43672,SCRIB;44228,p.R148Q;tmVar:p|SUB|R|148|Q;HGVS:p.R148Q;VariantGroup:8;CorrespondingGene:1857;RS#:764021343;CA#:2727085,p.G644V;tmVar:p|SUB|G|644|V;HGVS:p.G644V;VariantGroup:9;CorrespondingGene:23513;RS#:201104891;CA#:187609256,0
"This is a rare variant with a reported frequency of T = 0.0006/3 (1000 Genomes), T = 0.0005/6 (GO-@GENE$), and T = 0.0005/66 (TOPMED) in various databases. Neither the @VARIANT$ nor the @VARIANT$ variant has been reported as a mutation of a compound heterozygote in patients diagnosed with a myopathy secondary to mutations in either the @GENE$ or CAPN genes.",6180278,ESP;148713,DES;56469,rs138172448;tmVar:rs138172448;VariantGroup:2;CorrespondingGene:825;RS#:138172448,rs144901249;tmVar:rs144901249;VariantGroup:3;CorrespondingGene:1674;RS#:144901249,0
"The nucleotide sequence showed a @VARIANT$ (c.769G>C) of the coding sequence in exon 7 of @GENE$, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic @VARIANT$ (c.511C>T) of the coding sequence in exon 3 of @GENE$, which results in the substitution of Arg at residue 171 to Cys.",3842385,EDA;1896,WNT10A;22525,G to C transition at nucleotide 769;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,C to T transition at nucleotide 511;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous @GENE$ mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of GJB2 in 3 simplex families (235delC/N166S, 235delC/A194T and @VARIANT$/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"Only 9 mutations previously reported as recurrent were detected in our series of patients (i.e. 11% of the mutations), specifically, c.1996C>T, c.223delG, c.1556G>A, c.494C>T, c.3719G>A and @VARIANT$ in @GENE$, c.238_239dupC in USH1C, and c.2299delG and @VARIANT$ in @GENE$. Therefore, in the process of designing any strategy for USH molecular diagnosis, taking into account the high prevalence of novel mutations appears to be of major importance.",3125325,MYO7A;219,USH2A;66151,c.5749G>T;tmVar:c|SUB|G|5749|T;HGVS:c.5749G>T;VariantGroup:155;CorrespondingGene:4647;RS#:780609120;CA#:224854968,c.10712C>T;tmVar:c|SUB|C|10712|T;HGVS:c.10712C>T;VariantGroup:83;CorrespondingGene:7399;RS#:202175091;CA#:262060,0
"Subsequently, genetic testing for the LQT1, LQT2, LQT3, LQT5, and LQT6 genes identified a heterozygous c.3092_3096dup (@VARIANT$) mutation of the KCNH2 gene (LQT2) and a heterozygous c.170T > C (@VARIANT$) unclassified variant (UV) of the KCNE2 gene (LQT6). The UV (missense mutation) of the KCNE2 gene is likely a pathogenic mutation, what results in the digenic inheritance of @GENE$ and @GENE$. Genetic screening revealed that both sons are not carrying the familial KCNH2 mutation.",6610752,LQT2;201,LQT6;71688,p.Arg1033ValfsX26;tmVar:p|FS|R|1033|V|26;HGVS:p.R1033VfsX26;VariantGroup:1;CorrespondingGene:3757,p.Ile57Thr;tmVar:p|SUB|I|57|T;HGVS:p.I57T;VariantGroup:0;CorrespondingGene:9992;RS#:794728493,0
"The proband from Family 1 is consistent with the H1 haplotype based on the presence of homozygous genotypes for rs4935 and @VARIANT$ although this is not definitive because the rs10277 and rs1065154 polymorphisms were not covered. The haplotype of the proband from Family 2 could not be determined based on the available genotype data. For Family 3, sequencing data were available for four family members, and we manually reconstructed the haplotype assuming the minimal number of recombinations. The result indicated that Family 3's haplotype was consistent with either the H2 or the H5 haplotype described in the study by Lucas et al.. On the basis of these results, our three families have at least two different haplotypes associated with the SQSTM1 mutation, indicating that this unique phenotype is not a haplotype-specific effect, as well as demonstrating that these families are not remotely related to each other.   Discussion We present the first detailed clinical and pathologic data from three unrelated families with predominant distal myopathy associated with a known pathologic variant in @GENE$ (p.Pro392Leu) and a variant in @GENE$ (@VARIANT$).",5868303,SQSTM1;31202,TIA1;20692,rs4797;tmVar:rs4797;VariantGroup:0;CorrespondingGene:8878;RS#:4797,p.Asn357Ser;tmVar:p|SUB|N|357|S;HGVS:p.N357S;VariantGroup:5;CorrespondingGene:7072;RS#:116621885;CA#:1697407,0
"On the other hand, two missense mutations of the @GENE$ gene were identified in two families, SLC26A4: c.1300G>A (p.434A>T), EPHA2: c.1063G>A (p.G355R) and @GENE$: @VARIANT$ (p.410T>M), EPHA2: c.1532C>T (@VARIANT$) (Fig. 6a, b).",7067772,EPHA2;20929,SLC26A4;20132,c.1229C>A;tmVar:c|SUB|C|1229|A;HGVS:c.1229C>A;VariantGroup:21;CorrespondingGene:5172,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Surprisingly, we identified two missense mutations in the proband: NM_001257180.2, exon10, @VARIANT$, p.His596Arg in @GENE$ (Figure 1c) and NM_002609.4, exon3, c.317G>C, @VARIANT$, rs544478083 in @GENE$ (Figure 1d). Subsequently, we further detected the distribution of the two variants in this family and found that the proband's father carried the SLC20A2 mutation, the proband's mother and maternal grandfather carried the PDGFRB variant (Figure 1a).",8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,1
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (@VARIANT$) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,p.His596Arg;tmVar:p|SUB|H|596|R;HGVS:p.H596R;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"We finally found evidence of four potential novel candidate genes contributing to IHH: coiled-coil domain containing 88C (CCDC88C), cell adhesion associated, oncogene regulated (CDON), glutamate decarboxylase like 1 (GADL1), and sprouty related EVH1 domain containing 3 (@GENE$). The CCDC88C missense variant p. Arg1299Cys was heterozygous in case P05. CCDC88Cis a negative regulator of the Wnt signaling pathway, and bi-allelic mutations in CCDC88C were linked to midline brain malformation. Of note, the same variant @VARIANT$ was previously reported in a patient affected with pituitary stalk interruption syndrome (PSIS) with an etiologic overlap of IHH, who carried a mutationinan IHH-causative gene, @GENE$ (TACR3). Similarly, the CCDC88C-mutated case P05 in our study carried additional variants in DCC netrin 1 receptor (DCC)p. Gln91Arg, and FGFR1 @VARIANT$, implying that the deleterious variants in CCDC88C act together with other variants to cause IHH through a digenic/oligogenic model.",8152424,SPRED3;28061,tachykinin receptor 3;824,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,c.1664-2A>C;tmVar:c|SUB|A|1664-2|C;HGVS:c.1664-2A>C;VariantGroup:25;CorrespondingGene:2260,0
"33         Family 22 presented a complex case with three pathogenic alleles in the parents, among which the @GENE$: @VARIANT$ (p.S1448F) variant was a known pathogenic variant for adult-onset manifestation, while the foetal PKD (22.1) was inferred to have been caused by the compound heterozygous variants @GENE$: c.1675C > T (p.R559W) and PKHD1: c.7942G > A (@VARIANT$), which were inherited from the mother and the father, respectively (Figure 3).",8256360,PKD1;250,PKHD1;16336,c.4343C > T;tmVar:c|SUB|C|4343|T;HGVS:c.4343C>T;VariantGroup:8;CorrespondingGene:5310;RS#:546332839;CA#:7832402,p.G2648S;tmVar:p|SUB|G|2648|S;HGVS:p.G2648S;VariantGroup:6;CorrespondingGene:5314;RS#:139555370;CA#:149529,0
"Patient P0432 has a c.4030_4037delATGGCTGG (@VARIANT$) mutation in @GENE$ and a missense mutation in @GENE$ (@VARIANT$), but his father, who has neither deafness nor retinitis pigmentosa, also carries these two mutations, and his clinically affected sister does not carry the mutation in CDH23.",3125325,USH2A;66151,CDH23;11142,p.M1344fsX42;tmVar:p|FS|M|1344||42;HGVS:p.M1344fsX42;VariantGroup:306;CorrespondingGene:26798,p.R1189W;tmVar:p|SUB|R|1189|W;HGVS:p.R1189W;VariantGroup:61;CorrespondingGene:64072;RS#:745855338;CA#:5544764,1
"In this line, an increased side chain polarity associated with amino acid substitution @VARIANT$ could also interfere protein interactions involving the first PITX2 transcriptional inhibitory domain, leading to a functional alteration. Additional studies are required to evaluate these hypotheses. Interestingly, according to Ensembl Regulatory Build, FOXC2 variants @VARIANT$ (synonymous) and c.*38T>G (non coding 3' UTR) also mapped at a promoter, which overlapped with FOXC2 and @GENE$-@GENE$ genes.",6338360,FOXC2;21091,AS1;736,p.(A188T);tmVar:p|SUB|A|188|T;HGVS:p.A188T;VariantGroup:5;CorrespondingGene:5308;RS#:77144743;CA#:203139,p.S36S;tmVar:p|SUB|S|36|S;HGVS:p.S36S;VariantGroup:0;CorrespondingGene:103752587;RS#:138318843;CA#:8218260,0
"For example, two variants in proband P15, p. Ala103Val in PROKR2 and p. Tyr503His in DDB1 and CUL4 associated factor 17 (DCAF17), were inherited from unaffected father, while @GENE$ @VARIANT$ variant was inherited from unaffected mother. Proband 17 inherited @GENE$ @VARIANT$ and CDON p. Val969Ile variants from his unaffected father and mother, respectively.",8152424,DMXL2;41022,CHD7;19067,p. Gln1626His;tmVar:p|SUB|Q|1626|H;HGVS:p.Q1626H;VariantGroup:10;CorrespondingGene:23312;RS#:754695396;CA#:7561930,p. Trp1994Gly;tmVar:p|SUB|W|1994|G;HGVS:p.W1994G;VariantGroup:14;CorrespondingGene:55636,0
"  Digenic inheritances of @GENE$/@GENE$ and GJB2/GJB3 (group II). (A) In addition to @VARIANT$ in GJB2, the de novo variant of MITF, @VARIANT$ was identified in SH107-225. (B) There was no GJB6 large deletion within the DFNB1 locus.",4998745,GJB2;2975,MITF;4892,c.235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:10;CorrespondingGene:2706;RS#:80338943,p.R341C;tmVar:p|SUB|R|341|C;HGVS:p.R341C;VariantGroup:7;CorrespondingGene:161497;RS#:1359505251,0
"Variants in all known WS candidate genes (@GENE$, EDNRB, MITF, PAX3, SOX10, SNAI2, and TYRO3) were searched and a novel rare heterozygous deletion mutation (c.965delA; @VARIANT$) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; @VARIANT$) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDN3;88,MITF;4892,p.Asn322fs;tmVar:p|FS|N|322||;HGVS:p.N322fsX;VariantGroup:3;CorrespondingGene:4286,p.Arg203Cys;tmVar:p|SUB|R|203|C;HGVS:p.R203C;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"Variants in all known WS candidate genes (EDN3, EDNRB, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the @GENE$ gene in both patients. Moreover, heterozygous missense variants in SNAI3 (c.607C>T; p.Arg203Cys) and TYRO3 (c.1037T>A; @VARIANT$) gene was identified in the exome data of both patients.",7877624,TYRO3;4585,MITF;4892,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,p.Ile346Asn;tmVar:p|SUB|I|346|N;HGVS:p.I346N;VariantGroup:2;CorrespondingGene:7301;RS#:12148316;CA#:7494886,0
"Since the @GENE$ c.1664-2A>C variant was evaluated as pathogenic according to the ACMG guideline, this family might be considered as a case of monogenic inheritance. However, proband P05 also carried a paternal variant (@GENE$ p. Gln91Arg) and a maternal variant (CCDC88C @VARIANT$). Considering the facts that the loss-of-function mutations in FGFR1 were identified to act in concert with other gene defects and the CCDC88C p. Arg1299Cys variant was reported in a PSIS patient with an IHH-causative gene in a digenic manner, the possibility of oligogenic inheritance in family 05 cannot be ruled out.         Six families harbored only one variant of IHH genes, but none had sufficient evidence to be identified as monogenic models. Among these variants, one was frameshift variant, immunoglobulin superfamily member 10 (IGSF10) @VARIANT$, and the rest were missense variants.",8152424,FGFR1;69065,DCC;21081,p. Arg1299Cys;tmVar:p|SUB|R|1299|C;HGVS:p.R1299C;VariantGroup:4;CorrespondingGene:440193;RS#:142539336;CA#:7309192,p. Thr584Serfs*5;tmVar:p|FS|T|584|S|5;HGVS:p.T584SfsX5;VariantGroup:2;CorrespondingGene:285313;RS#:751845547;CA#:2670482,0
"Two different @GENE$ mutations (N166S and A194T) occurring in compound heterozygosity with the @VARIANT$ and 299delAT of @GENE$ were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/@VARIANT$).",2737700,GJB3;7338,GJB2;2975,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,A194T;tmVar:c|SUB|A|194|T;HGVS:c.194A>T;VariantGroup:4;CorrespondingGene:2707;RS#:117385606;CA#:118313,0
"            Three rare missense variants (R2034Q, L2118V, and @VARIANT$) of the SPG11 gene were found. The high detection rate of missense variants of this gene is probably due to the large size of the coding region; therefore, we suggest that these SPG11 variants are unlikely to be deleterious. Variants in the @GENE$ gene are most commonly associated with autosomal recessive spastic paraplegia, although homozygous variants have been recently identified in juvenile ALS, and heterozygous missense variants in sALS. Variants in UBQLN2 have been shown to be a cause of dominant X-linked ALS. A previously reported (M392V,) and a novel variant (Q84H) were found in the UBQLN2 gene. The novel @VARIANT$ variant affects the N-terminal ubiquitin-like domain of the ubiquilin-2 protein, which is involved in binding to proteasome subunits.  FUS variants have been mostly detected in familial ALS cases that are localized within the C-terminus of the @GENE$ protein.",6707335,SPG11;41614,FUS;2521,E2003D;tmVar:p|SUB|E|2003|D;HGVS:p.E2003D;VariantGroup:3;CorrespondingGene:80208;RS#:954483795,Q84H;tmVar:p|SUB|Q|84|H;HGVS:p.Q84H;VariantGroup:43;CorrespondingGene:29978,0
"To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of @GENE$ L117F, pendrin @VARIANT$, and pendrin @VARIANT$ mutations on @GENE$ interaction and internalization was examined.",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,F355L;tmVar:p|SUB|F|355|L;HGVS:p.F355L;VariantGroup:4;CorrespondingGene:1969;RS#:370923409,0
"Two affected (II-3 and III-9) individuals were selected for WES. +/+, wild-type; +/-, heterozygous for REEP4 c.109C>T. (b) Electropherograms of unaffected family member (II-2) and subject with @GENE$ (II-3). (c) Multiple sequence alignment shows evolutionary conservation of @VARIANT$ among vertebrates                @GENE$ missense variant A TOR2A nonsynonymous SNV (c.568C>T [NM_130459.3], @VARIANT$ [NP_569726.2]) was identified in three subjects with BSP and three asymptomatic members from a four generation pedigree (Figure 5; Tables 1, 5, 8 and S2; Data S1).",6081235,BSP+;3644,TOR2A;25260,Arg37;tmVar:p|Allele|R|37;VariantGroup:10;CorrespondingGene:80346;RS#:780399718,p.Arg190Cys;tmVar:p|SUB|R|190|C;HGVS:p.R190C;VariantGroup:12;CorrespondingGene:27433;RS#:376074923;CA#:5250615,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with @GENE$ @VARIANT$ and @GENE$ p.R408C with SETX @VARIANT$ and SETX p.T14I).,4293318,VAPB;36163,TAF15;131088,p.M170I;tmVar:p|SUB|M|170|I;HGVS:p.M170I;VariantGroup:45;CorrespondingGene:9217;RS#:143144050;CA#:9924276,p.I2547T;tmVar:p|SUB|I|2547|T;HGVS:p.I2547T;VariantGroup:58;CorrespondingGene:23064;RS#:151117904;CA#:233108,0
"This individual was also heterozygous for the common @GENE$ @VARIANT$ variant, and also carries a rare glycine decarboxylase (GLDC) c.2203G>T missense variant, possibly indicating a compromised FOCM in this patient. Interestingly, 2 unrelated patients harbor an identical extremely rare (gnomAD frequency 1/276 358) missense variant (@VARIANT$; p.Val2517Met) within the transmembrane receptor domain of the cadherin, EGF LAG seven-pass G-type receptor 1 (@GENE$) gene, which encodes a core protein of the PCP pathway (Figure 2E, Table S2 in Appendix S3).",5887939,MTHFR;4349,CELSR1;7665,c.677C>T;tmVar:c|SUB|C|677|T;HGVS:c.677C>T;VariantGroup:27;CorrespondingGene:4524;RS#:1801133;CA#:170990,c.7549G>A;tmVar:c|SUB|G|7549|A;HGVS:c.7549G>A;VariantGroup:14;CorrespondingGene:9620;RS#:1261513383,0
"Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and 299delAT of @GENE$ in 3 simplex families (235delC/N166S, 235delC/A194T and 299delAT/A194T). In family A, a profoundly hearing impaired proband was found to be heterozygous for a novel A to G transition at nucleotide position 497 of @GENE$, resulting in an asparagine into serine substitution in codon 166 (@VARIANT$) and for the @VARIANT$ of GJB2 (Fig. 1b, d).",2737700,GJB2;2975,GJB3;7338,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,235delC;tmVar:c|DEL|235|C;HGVS:c.235delC;VariantGroup:1;CorrespondingGene:2706;RS#:80338943,0
"  In patient AVM427, the de novo heterozygous missense variant @VARIANT$ (p.Asp1148Tyr) was identified in ZFYVE16 (table 1), which encodes an endosomal protein also known as endofin. ZFYVE16 is an SMAD anchor that facilitates @GENE$ phosphorylation, thus activating BMP signalling. In addition to Smad1-mediated BMP signalling, @GENE$ also interacts with Smad4 to mediate Smad2-Smad4 complex formation and facilitate TGF-beta signalling, indicating a regulatory role in BMP/TGF-beta signalling (figure 3). Other potential dominant genes with incomplete penetrance We also examined other inherited dominant pathogenic variants potentially involving LoF. Evidence of involvement in the pathogenesis of AVM was found in patient AVM312, who carried a paternally inherited heterozygous nonsense variant, c.1891G>T (p.Glu631Ter), in EGFR (table 1). Oncogenic EGFR stimulates angiogenesis via the VEGF pathway. As a truncated germline EGFR variant has not been reported in humans, c.1891G>T (@VARIANT$) in patient AVM312 was classified as likely pathogenic and EGFR as a candidate gene due to the vital role of EGFR in EGF and VEGF signalling.",6161649,SMAD1;21196,ZFYVE16;8826,c.3442G>T;tmVar:c|SUB|G|3442|T;HGVS:c.3442G>T;VariantGroup:3;CorrespondingGene:9765,p.Glu631Ter;tmVar:p|SUB|E|631|X;HGVS:p.E631X;VariantGroup:8;RS#:909905659,0
Two SALS patients carried multiple ALS-associated variants that are rare in population databases (ANG p.K41I with VAPB p.M170I and @GENE$ @VARIANT$ with SETX p.I2547T and @GENE$ @VARIANT$).,4293318,TAF15;131088,SETX;41003,p.R408C;tmVar:p|SUB|R|408|C;HGVS:p.R408C;VariantGroup:9;CorrespondingGene:8148;RS#:200175347;CA#:290041127,p.T14I;tmVar:p|SUB|T|14|I;HGVS:p.T14I;VariantGroup:28;CorrespondingGene:4094;RS#:1219381953,1
"The ages of onset of the patients with the @GENE$ variants reported in this study were later than juvenile ALS onset, which generally manifests before 25 years of age. Previous studies suggested that heterozygous variants in the ALS2 may be causative for adult-onset sALS.  MATR3 encodes three protein isoforms that have been described as nuclear-matrix and DNA/RNA binding proteins involved in transcription and stabilization of mRNA. In the present study, two novel heterozygous variants (P11S, @VARIANT$) were detected. The P11S variant affects the b isoform of the @GENE$ protein (NM_001194956 and NP_001181885), contributing to splicing alteration of other isoforms. Further evidence is required to elucidate the mechanism of pathogenicity of these alterations. We discovered several variants in ALS candidate and risk genes. In a patient with LMN-dominant ALS with slow progression, we found two novel variants (@VARIANT$ and G4290R) in the DYNC1H1 gene.",6707335,ALS2;23264,MATR3;7830,S275N;tmVar:p|SUB|S|275|N;HGVS:p.S275N;VariantGroup:9;CorrespondingGene:80208;RS#:995711809,T2583I;tmVar:p|SUB|T|2583|I;HGVS:p.T2583I;VariantGroup:31;CorrespondingGene:1778,0
"We identified a novel compound heterozygous variant in BBS1 c.1285dup (p.(Arg429Profs*72); a likely pathogenic novel variant affecting the conserved residue 354 in the functional domain of @GENE$ (c.1062C > G; @VARIANT$); a pathogenic new homozygous nucleotide change in @GENE$ that leads to a stop codon in position 255, c.763A > T, and a likely pathogenic homozygous substitution c.1235G > T in BBS6, leading to the change p.(@VARIANT$).",6567512,BBS2;12122,BBS7;12395,p.(Asn354Lys);tmVar:p|SUB|N|354|K;HGVS:p.N354K;VariantGroup:23;CorrespondingGene:583,Cys412Phe;tmVar:p|SUB|C|412|F;HGVS:p.C412F;VariantGroup:15;CorrespondingGene:8195;RS#:1396840386,0
"Variants in all known WS candidate genes (EDN3, @GENE$, MITF, PAX3, SOX10, SNAI2, and @GENE$) were searched and a novel rare heterozygous deletion mutation (@VARIANT$; p.Asn322fs) was identified in the MITF gene in both patients. Moreover, heterozygous missense variants in SNAI3 (@VARIANT$; p.Arg203Cys) and TYRO3 (c.1037T>A; p.Ile346Asn) gene was identified in the exome data of both patients.",7877624,EDNRB;89,TYRO3;4585,c.965delA;tmVar:c|DEL|965|A;HGVS:c.965delA;VariantGroup:4;CorrespondingGene:4286,c.607C>T;tmVar:c|SUB|C|607|T;HGVS:c.607C>T;VariantGroup:1;CorrespondingGene:333929;RS#:149676512;CA#:8229366,0
"As shown in Table 3, all male individuals carrying the @GENE$-Q1916R mutation with (II-4, III-1, III-5 and IV-3) or without (III-7) concomitant SCN5A-R1193Q showed the ERS phenotypes. The female CACNA1C-@VARIANT$ mutation carriers with @GENE$-@VARIANT$ variant (II-3, II-6, III-4 and IV-1) were not affected, while the female member only carrying the CACNA1C-Q1916R mutation (IV-4) showed the ER ECG pattern.",5426766,CACNA1C;55484,SCN5A;22738,Q1916R;tmVar:p|SUB|Q|1916|R;HGVS:p.Q1916R;VariantGroup:4;CorrespondingGene:775;RS#:186867242;CA#:6389963,R1193Q;tmVar:p|SUB|R|1193|Q;HGVS:p.R1193Q;VariantGroup:7;CorrespondingGene:6331;RS#:41261344;CA#:17287,0
"Compared to WT (wild-type) proteins, we found that the ability of GFP-CYP1B1 @VARIANT$ and GFP-@GENE$ E229K to immunoprecipitate HA-TEK @VARIANT$ and HA-@GENE$ Q214P, respectively, was significantly diminished.",5953556,CYP1B1;68035,TEK;397,A115P;tmVar:p|SUB|A|115|P;HGVS:p.A115P;VariantGroup:0;CorrespondingGene:1545;RS#:764338357;CA#:1620052,E103D;tmVar:p|SUB|E|103|D;HGVS:p.E103D;VariantGroup:2;CorrespondingGene:7010;RS#:572527340;CA#:5015873,0
"The nucleotide sequence showed a G to C transition at nucleotide 769 (@VARIANT$) of the coding sequence in exon 7 of EDA, which results in the substitution of Gly at residue 257 to Arg. Additionally, the nucleotide sequence showed a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of WNT10A, which results in the substitution of Arg at residue 171 to Cys. DNA sequencing of the parents' genome revealed that both mutant alleles were from their mother (Fig. 2A), who carried a heterozygous EDA mutation (c.769G>C) and a heterozygous WNT10A c.511C>T mutation, and showed absence of only the left upper lateral incisor without other clinical abnormalities. No mutations in these genes were found in the father.     Sequence analyses of EDA and WNT10A genes. (A) The @GENE$ mutation c.769G>C and @GENE$ mutation @VARIANT$ were found in patient N1, who inherited the mutant allele from his mother.",3842385,EDA;1896,WNT10A;22525,c.769G>C;tmVar:c|SUB|G|769|C;HGVS:c.769G>C;VariantGroup:0;CorrespondingGene:1896;RS#:1057517882;CA#:16043329,c.511C>T;tmVar:c|SUB|C|511|T;HGVS:c.511C>T;VariantGroup:3;CorrespondingGene:80326;RS#:116998555;CA#:2113955,0
"Given the reported normal function of pendrin L117F and @GENE$ S166N as an anion exchanger, compromised regulatory machinery of pendrin function may cause the observed symptoms. To examine whether EphA2 is involved in dysfunction of pendrin caused by these amino acid substitutions, the effect of pendrin L117F, pendrin @VARIANT$, and pendrin F355L mutations on EphA2 interaction and internalization was examined. While the amount of co-precipitated pendrin mutants with EphA2 was comparable to that of wild type (wt) pendrin (Fig. 5c, d), the S166N mutant failed to be internalized after ephrin-B2 stimulation (Fig. 5e, f). Taken together, these results further demonstrate that @GENE$ could control both pendrin recruitment to the plasma membrane and pendrin exclusion from the plasma membrane.   EPHA2 mutations in pendred syndrome patients Identification and characterization of EphA2 mutation from hearing loss patients with EVA. a, b Pedigree chart of the patients carrying mono-allelic EPHA2 and SLC26A4 mutations. c Audiograms of the patient with mono-allelic EPHA2 @VARIANT$ and SLC26A4 p.T410M mutations.",7067772,pendrin;20132,EphA2;20929,S166N;tmVar:p|SUB|S|166|N;HGVS:p.S166N;VariantGroup:22;CorrespondingGene:23985,p.T511M;tmVar:p|SUB|T|511|M;HGVS:p.T511M;VariantGroup:5;CorrespondingGene:1969;RS#:55747232;CA#:625151,0
"Moller et al. reported an index case with digenic variants in @GENE$ (@VARIANT$) and MYBPC3 (R326Q), both encoding sarcomeric proteins that are likely to affect its structure when mutated. Petropoulou et al. reported a family severely affected by DCM and who had two digenic variations in MYH7 (Asp955Asn) and @GENE$ (@VARIANT$), both sarcomeric genes.",6359299,MYH7;68044,TNNT2;68050,L1038P;tmVar:p|SUB|L|1038|P;HGVS:p.L1038P;VariantGroup:8;CorrespondingGene:4625;RS#:551897533;CA#:257817954,Asn83His;tmVar:p|SUB|N|83|H;HGVS:p.N83H;VariantGroup:4;CorrespondingGene:7139;RS#:1060500235,0
"The T338I and @VARIANT$ variants affect the conserved central coiled-coil rod domain of the protein mediating dimerization; therefore, we suggest their potential deleterious effect on the protein. In the individual carrying the @VARIANT$ NEFH variant, an additional novel alteration (C335R) was detected in the @GENE$ gene. Loss-of-function GRN variants are primarily considered to cause frontotemporal lobar degeneration, but there is evidence that missense GRN variants are also linked to the pathogenesis of ALS. The novel GRN variant reported in this study results in a cysteine-to-arginine change in the cysteine-rich granulin A domain. Four cases were identified to carry SQSTM1 variants: the P392L in two cases and the E389Q and R393Q in single patients. All three alterations are located within the C-terminal ubiquitin-associated (UBA) end of the sequestome 1 protein. Variants of the @GENE$ gene were originally reported in Paget's disease of bone.",6707335,GRN;1577,SQSTM1;31202,R148P;tmVar:p|SUB|R|148|P;HGVS:p.R148P;VariantGroup:14;CorrespondingGene:2521;RS#:773655049,P505L;tmVar:p|SUB|P|505|L;HGVS:p.P505L;VariantGroup:22;CorrespondingGene:4744;RS#:1414968372,0
"The nucleotide sequence showed a T deletion at nucleotide 252 (c.252DelT) of the coding sequence in exon 1 of @GENE$; this leads to a frame shift from residue 84 and a premature termination at residue 90. Additionally, a monoallelic C to T transition at nucleotide 511 (c.511C>T) of the coding sequence in exon 3 of @GENE$ was detected, this leads to the substitution of Arg at residue 171 to Cys. Analyses of his parents' genome showed that the mutant EDA allele was from his mother (Fig. 2C), however, we were unable to screen for WNT10A mutations because of insufficient DNA.     ""S2"" is a 17-year-old boy who had curly hair, 17 missing permanent teeth and hypohidrosis, his skin and nails were normal (Fig. 1 and Table 1). The p.Arg153Cys (@VARIANT$) mutation was found in exon 3 of EDA, it results in the substitution of Arg at residue 153 to Cys. Moreover, a heterozygous @VARIANT$ (c.637G>A) mutation was detected in exon 3 of WNT10A, this leads to the substitution of Gly at residue 213 to Ser.",3842385,EDA;1896,WNT10A;22525,c.457C>T;tmVar:c|SUB|C|457|T;HGVS:c.457C>T;VariantGroup:6;CorrespondingGene:1896;RS#:397516662(Expired),p.Gly213Ser;tmVar:p|SUB|G|213|S;HGVS:p.G213S;VariantGroup:4;CorrespondingGene:80326;RS#:147680216;CA#:211313,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation @VARIANT$ (p.His596Arg) in @GENE$ and the SNP (rs544478083) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the SLC20A2 c.1787A>G (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic. The proband's mother with the PDGFRB c.317G>C (@VARIANT$) variant showed very slight calcification and was clinically asymptomatic.,8172206,SLC20A2;68531,PDGFRB;1960,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,p.Arg106Pro;tmVar:p|SUB|R|106|P;HGVS:p.R106P;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,0
"@GENE$ mutations were the second most prevalent genetic alterations in DH: five different heterozygous variants were found in 5/21 patients (23.8%), and these often cooccurred with DUOX2 or DUOXA2 mutations. DUOX2 and TG mutation locations varied in the corresponding proteins (Figure 2). Additionally, three DUOXA2 variants were found in 3/21 patients (14%), and a known heterozygous variant in SLC26A4 was found in one patient. No mutations in SLC5A5, TPO, or IYD gene exons were found. Most of the variants presented as heterozygous in patients. Only three variants were homozygous in three patients: (1) DUOX2: @VARIANT$ (p.M927V) in one patient, (2) @GENE$:c.3329G>A (p.R1110Q) in one patient, and (3) DUOXA2: @VARIANT$ (p.Y138X) in one patient.",6098846,TG;2430,DUOX2;9689,c.2779A>G;tmVar:c|SUB|A|2779|G;HGVS:c.2779A>G;VariantGroup:27;CorrespondingGene:50506;RS#:755186335;CA#:7538155,c.413dupA;tmVar:c|DUP|413|A|;HGVS:c.413dupA;VariantGroup:19;CorrespondingGene:405753;RS#:1085307064,0
"      WES revealed heterozygous mutations in two genes known to affect hypothalamic and pituitary development: c.253C>T;@VARIANT$ in @GENE$ (MIM 607123; NM_144773.2; rs141090506) inherited from an unaffected mother and c.1306A>G;p.I436V in @GENE$ (MIM 606417; NM_018117.11; @VARIANT$) inherited from an unaffected father, both confirmed by Sanger sequencing (Fig. 1).",5505202,PROKR2;16368,WDR11;41229,p.R85C;tmVar:p|SUB|R|85|C;HGVS:p.R85C;VariantGroup:1;CorrespondingGene:128674;RS#:74315418,rs34602786;tmVar:rs34602786;VariantGroup:3;CorrespondingGene:55717;RS#:34602786,1
"To investigate the role of @GENE$ variations along with GJB2 mutations for a possible combinatory allelic disease inheritance, we have screened patients with heterozygous GJB2 mutations for variants in Cx31 by sequencing. Analysis of the entire coding region of the Cx31 gene revealed the presence of two different missense mutations (N166S and A194T) occurring in compound heterozygosity along with the 235delC and @VARIANT$ of @GENE$ in 3 simplex families (235delC/@VARIANT$, 235delC/A194T and 299delAT/A194T).",2737700,GJB3;7338,GJB2;2975,299delAT;tmVar:c|DEL|299|AT;HGVS:c.299delAT;VariantGroup:12;CorrespondingGene:2706,N166S;tmVar:p|SUB|N|166|S;HGVS:p.N166S;VariantGroup:0;CorrespondingGene:2707;RS#:121908851;CA#:118311,0
"Both mutations are novel and whilst a different mutation, R80W, has been reported in @GENE$, further evidence to support the pathogenicity of @VARIANT$ is lacking. The siblings we describe with the @GENE$ P291fsinsC and HNF4A @VARIANT$ mutations are the first cases of digenic transcription factor MODY where both mutations have previously been reported as being pathogenic.",4090307,HNF4A;395,HNF1A;459,E508K;tmVar:p|SUB|E|508|K;HGVS:p.E508K;VariantGroup:0;CorrespondingGene:6927;RS#:483353044;CA#:289173,R127W;tmVar:p|SUB|R|127|W;HGVS:p.R127W;VariantGroup:3;CorrespondingGene:3172;RS#:370239205;CA#:9870226,0
"Using these filtering settings, no variants in @GENE$ or @GENE$ were detected in any of our control datasets which emphasizes that the presence of rare double hits in our FTLD-TDP cohort is unlikely to have occurred by chance alone. Comparison of sequence traces of OPTN exon 8 (harboring the @VARIANT$ mutation) in gDNA and mRNA prepared from cerebellar cortex of case A showed the absence of mutant RNA (T-allele) suggesting the degradation of mutant RNA by nonsense mediated decay (Figure 1c). A similar analysis of OPTN exon 14 (harboring the @VARIANT$) mutation showed significantly reduced amounts of the wild-type (C-allele) in the cDNA sequence suggesting that the missense variant was inherited in trans with respect to the OPTN nonsense mutation (Figure 1c).",4470809,OPTN;11085,TBK1;22742,p.Gln235*;tmVar:p|SUB|Q|235|*;HGVS:p.Q235*;VariantGroup:26;CorrespondingGene:29110,p.Ala481Val;tmVar:p|SUB|A|481|V;HGVS:p.A481V;VariantGroup:1;CorrespondingGene:10133;RS#:377219791;CA#:5410970,0
         DISCUSSION We present a Chinese family with PFBC in which the previously reported heterozygous mutation c.1787A>G (p.His596Arg) in SLC20A2 and the SNP (@VARIANT$) c.317G>C (p.Arg106Pro) in @GENE$ were identified. The proband's father with the @GENE$ @VARIANT$ (p.His596Arg) mutation showed obvious brain calcification but was clinically asymptomatic.,8172206,PDGFRB;1960,SLC20A2;68531,rs544478083;tmVar:rs544478083;VariantGroup:1;CorrespondingGene:5159;RS#:544478083,c.1787A>G;tmVar:c|SUB|A|1787|G;HGVS:c.1787A>G;VariantGroup:2;CorrespondingGene:6575,0