VCI/split_evidence_score/test.csv

entry_index,variant,hgnc_gene,disease,mondo_id,assertion,mode_inheritance,expert_panel,pub_date,evidence_code,met_status,pmid,comments,summary,summary_comments,path
76,NM_000277.1(PAH):c.926C>T (p.Ala309Val),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4,met,PubMed:26666653,"Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.","Single patient with classic PKU (>1200umol/L), BH4 defect not excluded","Single patient with classic PKU (>1200umol/L), BH4 defect not excluded Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
592,NM_000277.2(PAH):c.164T>C (p.Phe55Ser),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PP4,met,PubMed:26666653,"Phe55Ser identified in 1 patient with classic PKU. A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. They represented mixed origin people from 20 French Centers for Inborn Errors of Metabolism. According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories. classical phenylketonuria (cPKU, Phe > 1200 μmol/L).",Identified in 1 French patient with classic PKU. BH4 deficiency not assessed. PMID: 26666653,"Identified in 1 French patient with classic PKU. BH4 deficiency not assessed. PMID: 26666653 Phe55Ser identified in 1 patient with classic PKU. A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. They represented mixed origin people from 20 French Centers for Inborn Errors of Metabolism. According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories. classical phenylketonuria (cPKU, Phe > 1200 μmol/L).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
615,NM_000277.2(PAH):c.632delC (p.Pro211Hisfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-17,PP4,met,PubMed:26666653,Single patient,"Described in multiple independent patients, all with classic PKU (Phe >1200umol/L), BH4 defect not specifically excluded in any pub. (Guldberg, 1996;  PMID: 26413448;  PMID: 26666653; Sarkissian, 2011)","Described in multiple independent patients, all with classic PKU (Phe >1200umol/L), BH4 defect not specifically excluded in any pub. (Guldberg, 1996;  PMID: 26413448;  PMID: 26666653; Sarkissian, 2011) Single patient",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
615,NM_000277.2(PAH):c.632delC (p.Pro211Hisfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-17,PP4,met,PubMed:26413448,single homozygous patient with classic PKU,"Described in multiple independent patients, all with classic PKU (Phe >1200umol/L), BH4 defect not specifically excluded in any pub. (Guldberg, 1996;  PMID: 26413448;  PMID: 26666653; Sarkissian, 2011)","Described in multiple independent patients, all with classic PKU (Phe >1200umol/L), BH4 defect not specifically excluded in any pub. (Guldberg, 1996;  PMID: 26413448;  PMID: 26666653; Sarkissian, 2011) single homozygous patient with classic PKU",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
625,NM_000277.2(PAH):c.785T>G (p.Val262Gly),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4,met,PubMed:26666653,"A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories. V262G was observed in 1 patient with classic PKU.",V262G observed in 1 patient with classic PKU. BH4 deficiencies not assessed. PMID: 26666653.,"V262G observed in 1 patient with classic PKU. BH4 deficiencies not assessed. PMID: 26666653. A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories. V262G was observed in 1 patient with classic PKU.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
665,NM_000277.2(PAH):c.127G>T (p.Glu43Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PP4,met,PubMed:26503515,Variant is reported in 2 patients from mainland China in a cohort study. BH4 deficiency not ruled out.,, Variant is reported in 2 patients from mainland China in a cohort study. BH4 deficiency not ruled out.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
671,NM_000277.2(PAH):c.493G>C (p.Ala165Pro),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-04-07,PP4,met,PubMed:26666653,"detected in 1 patient with mild PKU (mPKU, 600 < Phe < 1200 μmol/L). BH4 deficiency not assessed/stated.",detected in 1 patient with mild PKU (PMID: 26666653). BH4 deficiency not assessed/stated.,"detected in 1 patient with mild PKU (PMID: 26666653). BH4 deficiency not assessed/stated. detected in 1 patient with mild PKU (mPKU, 600 < Phe < 1200 μmol/L). BH4 deficiency not assessed/stated.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
687,NM_000277.2(PAH):c.196G>T (p.Glu66Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PP4,met,PubMed:26666653,"The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120270); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID ) c. 1315+1G>A variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported in one proband with classic PKU (plasma phenylalanine levels > 1200umol/L) (PMID: 26666653),"The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported in one proband with classic PKU (plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120270); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID ) c. 1315+1G>A variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
717,NM_000277.2(PAH):c.931_932delCT (p.Leu311Glyfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PP4,met,PubMed:26666653,A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 <  Phe  < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 <  Phe  < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 <  Phe  < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded. A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 <  Phe  < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
718,NM_000277.2(PAH):c.837delC (p.Glu280Asnfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PP4,met,PubMed:26666653,A compound heterozygous proband with the c.837del variant (misidentified in this publication as His280Asnfs*61) was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,Two compound heterozygous probands have been described with the c.837del variant each with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,Two compound heterozygous probands have been described with the c.837del variant each with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded. A compound heterozygous proband with the c.837del variant (misidentified in this publication as His280Asnfs*61) was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
746,NM_000277.2(PAH):c.1163T>C (p.Val388Ala),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-07-19,PP4,met,PubMed:26666653,"The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
844,NM_000277.1(PAH):c.782G>C (p.Arg261Pro),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-11,PP4,met,PubMed:26666653,"Table1_p. [Ile65Thr]; [Arg261Pro]_pt has classic PKU and Total BH4 loading test not responding. ['According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories: mild hyperphenylalaninemia (mHP, 180 < Phe < 600 μmol/L); mild phenylketonuria (mPKU, 600 < Phe < 1200 μmol/L) and classical phenylketonuria (cPKU, Phe > 1200 μmol/L).']",Detected in 5 patients with PKU (PMID: 26666653). BH4 deficiency not ruled out.,"Detected in 5 patients with PKU (PMID: 26666653). BH4 deficiency not ruled out. Table1_p. [Ile65Thr]; [Arg261Pro]_pt has classic PKU and Total BH4 loading test not responding. ['According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories: mild hyperphenylalaninemia (mHP, 180 < Phe < 600 μmol/L); mild phenylketonuria (mPKU, 600 < Phe < 1200 μmol/L) and classical phenylketonuria (cPKU, Phe > 1200 μmol/L).']",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
858,NM_000277.2(PAH):c.155delT (p.Leu52Cysfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-16,PP4,met,PubMed:26666653,"This variant was reported in a patient with PKU who carried a second nonsense mutation in PAH (Arg261*), however BH4 deficiency was not ruled out.",," This variant was reported in a patient with PKU who carried a second nonsense mutation in PAH (Arg261*), however BH4 deficiency was not ruled out.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
954,NM_000277.2(PAH):c.169G>T (p.Glu57Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-02,PP4,met,PubMed:26666653,"The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1010,NM_000277.2(PAH):c.913-8A>G,PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-11-08,PP4,met,PubMed:26666653,A compound heterozygous proband with the c.913-8A>G variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with the c.913-8A>G variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with the c.913-8A>G variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded. A compound heterozygous proband with the c.913-8A>G variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1359,NM_000277.2(PAH):c.694C>T (p.Gln232Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-31,PP4,met,PubMed:30050108,"c.694C>T detected on 6 alleles. 796 unrelated patients were enrolled. Biochemical testing data, including plasma phenylalanine levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.",c.694C>T detected on 6 alleles in a PKU Chinese cohort.  PMID: 30050108,"c.694C>T detected on 6 alleles in a PKU Chinese cohort.  PMID: 30050108 c.694C>T detected on 6 alleles. 796 unrelated patients were enrolled. Biochemical testing data, including plasma phenylalanine levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1495,NM_000277.2(PAH):c.682G>A (p.Glu228Lys),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2020-06-26,PP4,met,PubMed:26666653,"A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. E228K was seen on 1 allele of a patient with classic PKU.",E228K seen in 1 patient with classic PKU. BH4 deficiency not assessed.,"E228K seen in 1 patient with classic PKU. BH4 deficiency not assessed. A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. E228K was seen on 1 allele of a patient with classic PKU.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1505,NM_000277.1(PAH):c.1180G>T (p.Asp394Tyr),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-07-10,PP4,met,PubMed:26666653,"364 hyperphenylalaninemic patients, including 42 siblings, were investigated. Asp394Tyr found in 2 patients.",Seen in 2 mild PKU patients. BH4 deficiency not ruled out.  PMID: 26666653,"Seen in 2 mild PKU patients. BH4 deficiency not ruled out.  PMID: 26666653 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. Asp394Tyr found in 2 patients.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1575,NM_000277.2(PAH):c.441+1G>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PP4,met,PubMed:26503515,Recurrent mutation among Chinese cases with classic PKU.,"Found in multiple probands with classic PKU, although BH4 deficiency does not appear to have been formally excluded.","Found in multiple probands with classic PKU, although BH4 deficiency does not appear to have been formally excluded. Recurrent mutation among Chinese cases with classic PKU.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1675,NM_000277.3(PAH):c.124_126del (p.Lys42del),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-16,PP4,met,PubMed:30050108,,"PP4_met: This variant was reported in 1 patient with PAH deficiency (PMID: 27243974) and 1 patient with classic phenylketonuria (PMID: 30050108)

27243974, Yubero - This variant was documented in 1 patient with PAH deficiency. To compare the diagnostic yield obtained after NGS, patients were classified into two groups depending on the level of evidence supporting the suspicion and independently of the NGS analysis results. Group 1 (n = 81) included patients who presented with consistent clinical and biochemical data supporting their having an IEM studied in the panel. This patient with this variant was a part of this group. Tetrahydrobiopterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

30050108, Li - This variant was documented in 1 patient with classic phenylketonuria. Tetrahydrobipterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity although that data was collected if available.","PP4_met: This variant was reported in 1 patient with PAH deficiency (PMID: 27243974) and 1 patient with classic phenylketonuria (PMID: 30050108)

27243974, Yubero - This variant was documented in 1 patient with PAH deficiency. To compare the diagnostic yield obtained after NGS, patients were classified into two groups depending on the level of evidence supporting the suspicion and independently of the NGS analysis results. Group 1 (n = 81) included patients who presented with consistent clinical and biochemical data supporting their having an IEM studied in the panel. This patient with this variant was a part of this group. Tetrahydrobiopterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

30050108, Li - This variant was documented in 1 patient with classic phenylketonuria. Tetrahydrobipterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity although that data was collected if available. ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1675,NM_000277.3(PAH):c.124_126del (p.Lys42del),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-16,PP4,met,PubMed:27243974,,"PP4_met: This variant was reported in 1 patient with PAH deficiency (PMID: 27243974) and 1 patient with classic phenylketonuria (PMID: 30050108)

27243974, Yubero - This variant was documented in 1 patient with PAH deficiency. To compare the diagnostic yield obtained after NGS, patients were classified into two groups depending on the level of evidence supporting the suspicion and independently of the NGS analysis results. Group 1 (n = 81) included patients who presented with consistent clinical and biochemical data supporting their having an IEM studied in the panel. This patient with this variant was a part of this group. Tetrahydrobiopterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

30050108, Li - This variant was documented in 1 patient with classic phenylketonuria. Tetrahydrobipterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity although that data was collected if available.","PP4_met: This variant was reported in 1 patient with PAH deficiency (PMID: 27243974) and 1 patient with classic phenylketonuria (PMID: 30050108)

27243974, Yubero - This variant was documented in 1 patient with PAH deficiency. To compare the diagnostic yield obtained after NGS, patients were classified into two groups depending on the level of evidence supporting the suspicion and independently of the NGS analysis results. Group 1 (n = 81) included patients who presented with consistent clinical and biochemical data supporting their having an IEM studied in the panel. This patient with this variant was a part of this group. Tetrahydrobiopterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

30050108, Li - This variant was documented in 1 patient with classic phenylketonuria. Tetrahydrobipterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity although that data was collected if available. ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1693,NM_000277.3(PAH):c.578_579CT[1] (p.Leu194fs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-30,PP4,met,PubMed:26666653,,At least one proband with this variant has been described (PMID: 26666653) with the classic PKU phenotype and PHE >1200umol/L. Exclusion of defects in BH4 cofactor metabolism was not reported.,At least one proband with this variant has been described (PMID: 26666653) with the classic PKU phenotype and PHE >1200umol/L. Exclusion of defects in BH4 cofactor metabolism was not reported. ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1695,NM_000277.3(PAH):c.648C>G (p.Tyr216Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-30,PP4,met,PubMed:26666653,,At least one proband with this variant has been described (PMID: 26666653) with the classic PKU phenotype and PHE >1200umol/L. Exclusion of defects in BH4 cofactor metabolism was not reported.,At least one proband with this variant has been described (PMID: 26666653) with the classic PKU phenotype and PHE >1200umol/L. Exclusion of defects in BH4 cofactor metabolism was not reported. ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5921,NM_000277.1:c.510-19_667del,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PP4,met,PubMed:23842451,"Data were collected from 183 patients in six Dutch university medical centres. Blood Phe concentrations in dried blood spots were measured by the patients’ respective centre laboratory according to standard quantitative methods, with the same method per patient. c.510-21_665del was detected in one patient with Phe level 855 at baseline (T=0).",c.510-21_665del was detected in one patient with Phe level 855. BH4 deficiency not reported/assessed. PMID: 23842451,"c.510-21_665del was detected in one patient with Phe level 855. BH4 deficiency not reported/assessed. PMID: 23842451 Data were collected from 183 patients in six Dutch university medical centres. Blood Phe concentrations in dried blood spots were measured by the patients’ respective centre laboratory according to standard quantitative methods, with the same method per patient. c.510-21_665del was detected in one patient with Phe level 855 at baseline (T=0).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
76,NM_000277.1(PAH):c.926C>T (p.Ala309Val),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3,met,PubMed:26666653,"Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.","Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T","Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
562,NM_000277.1:c.1285C>A,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3,met,PubMed:28982351,Patient 328 has genotype EX6-96A>G (VarID 590; P/LP)/p.Gln429Lys. Peripheral blood samples were collected from the patients and parents in each of the 643 core families.,Detected with EX6-96A>G (VarID 590; P/LP).,Detected with EX6-96A>G (VarID 590; P/LP). Patient 328 has genotype EX6-96A>G (VarID 590; P/LP)/p.Gln429Lys. Peripheral blood samples were collected from the patients and parents in each of the 643 core families.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
592,NM_000277.2(PAH):c.164T>C (p.Phe55Ser),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3,met,PubMed:26666653,Patient genotype: c. [164T>C]; [1066-11G>A].,"Detected with c.1066-11G>A, PMID: 26666653","Detected with c.1066-11G>A, PMID: 26666653 Patient genotype: c. [164T>C]; [1066-11G>A].",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
597,NM_000277.2(PAH):c.812A>G (p.His271Arg),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3,met,PubMed:26666653,Patient genotype: [His271Arg]; [Arg408Trp].,"Detected with R408W,  PMID: 26666653","Detected with R408W,  PMID: 26666653 Patient genotype: [His271Arg]; [Arg408Trp].",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
615,NM_000277.2(PAH):c.632delC (p.Pro211Hisfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-17,PM3,met,PubMed:26666653,in trans,"Homozygous (Bilgiari, 2015) and in trans with 1066-11G>A (pathogenic, Jeannesson-Thivisol, 2015)","Homozygous (Bilgiari, 2015) and in trans with 1066-11G>A (pathogenic, Jeannesson-Thivisol, 2015) in trans",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
615,NM_000277.2(PAH):c.632delC (p.Pro211Hisfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-17,PM3,met,PubMed:26413448,single patient described with classic PKU,"Homozygous (Bilgiari, 2015) and in trans with 1066-11G>A (pathogenic, Jeannesson-Thivisol, 2015)","Homozygous (Bilgiari, 2015) and in trans with 1066-11G>A (pathogenic, Jeannesson-Thivisol, 2015) single patient described with classic PKU",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
625,NM_000277.2(PAH):c.785T>G (p.Val262Gly),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3,met,PubMed:26666653,"c. [117C > G]; [785 T > G]/p. [Phe39Leu];[Val262Gly]. F39L, VarID 605, Pathogenic","V262G detected with F39L,  PMID: 26666653","V262G detected with F39L,  PMID: 26666653 c. [117C > G]; [785 T > G]/p. [Phe39Leu];[Val262Gly]. F39L, VarID 605, Pathogenic",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
655,NM_000277.2(PAH):c.386A>G (p.Asp129Gly),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3,met,PubMed:26666653,Patient genotype: c.194T>C;c.386A>G / p.(Ile65Thr);p.(Asp129Gly). Parental segregation not reported/performed.,Detected in trans with c.1066-11G>A PMID:27121329,Detected in trans with c.1066-11G>A PMID:27121329 Patient genotype: c.194T>C;c.386A>G / p.(Ile65Thr);p.(Asp129Gly). Parental segregation not reported/performed.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
674,NM_000277.2(PAH):c.521T>C (p.Ile174Thr),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-08,PM3,met,PubMed:23842451,"patient genotype: p.I174T/p.F299C (P/LP, 6 submitters)","detected with p.F299C (P/LP, 6 submitters) 23842451","detected with p.F299C (P/LP, 6 submitters) 23842451 patient genotype: p.I174T/p.F299C (P/LP, 6 submitters)",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
675,NM_000277.2(PAH):c.523C>T (p.Pro175Ser),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-08,PM3,met,PubMed:26322415,"Patient genotype: c.[523C>T ];[1238G>C], p.[P175S];[R413P]. All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.","detected in trans with p.R413P (P, 6 submitters)  PMID: 26322415","detected in trans with p.R413P (P, 6 submitters)  PMID: 26322415 Patient genotype: c.[523C>T ];[1238G>C], p.[P175S];[R413P]. All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
676,NM_000277.2(PAH):c.143T>C (p.Leu48Ser),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-08,PM3,met,PubMed:26322415,"Patient genotype: c.[143T>C];[739G>C], p.[L48S];[G247R] (LP, 2 submitters). All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.","detected in trans with p.G247R (LP, 2 submitters)  PMID: 26322415","detected in trans with p.G247R (LP, 2 submitters)  PMID: 26322415 Patient genotype: c.[143T>C];[739G>C], p.[L48S];[G247R] (LP, 2 submitters). All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
718,NM_000277.2(PAH):c.837delC (p.Glu280Asnfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PM3,met,PubMed:26666653,"The c.837del frameshift variant (in this publication misidentified as His280Asnfs*61) was observed in trans with the pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.837del frameshift variant has been observed in trans with pathogenic variants Val388Met (ClinVar 619, Pathogenic) and c.1315+1G>A (ClinVar 576, Pathogenic).","The c.837del frameshift variant has been observed in trans with pathogenic variants Val388Met (ClinVar 619, Pathogenic) and c.1315+1G>A (ClinVar 576, Pathogenic). The c.837del frameshift variant (in this publication misidentified as His280Asnfs*61) was observed in trans with the pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
843,NM_000277.2(PAH):c.547_548delGAinsTT (p.Glu183Leu),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-11,PM3,met,PubMed:26666653,"This variant has been observed in trans with the previously assessed pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608, Pathogenic).","This variant has been observed in trans with the previously assessed pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608, Pathogenic).","This variant has been observed in trans with the previously assessed pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608, Pathogenic). This variant has been observed in trans with the previously assessed pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608, Pathogenic).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1010,NM_000277.2(PAH):c.913-8A>G,PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-11-08,PM3,met,PubMed:26666653,"The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic). The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1052,NM_000277.3(PAH):c.460T>C (p.Tyr154His),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-12-22,PM3,met,PubMed:26322415,,"The PAH variant c.460T>C (p.Tyr154His) was found in trans with the PAH pathogenic variant c.331C>T (p.Arg111Ter)(ClinVar ID: 581) in a Chinese patient with classical PKU (Phe levels >20 mg/dl) . All mutations identified in patients were confirmed by analyzing parental DNA. (PM3 Points= 1*1=1) (PMID: 26322415). The PAH variant c.460T>C (p.Tyr154His) was found as a homozygous occurrence in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PM3 Points= 1*0.5=0.5) (PMID:16256386)
PM3 points awarded in total: 1.5","The PAH variant c.460T>C (p.Tyr154His) was found in trans with the PAH pathogenic variant c.331C>T (p.Arg111Ter)(ClinVar ID: 581) in a Chinese patient with classical PKU (Phe levels >20 mg/dl) . All mutations identified in patients were confirmed by analyzing parental DNA. (PM3 Points= 1*1=1) (PMID: 26322415). The PAH variant c.460T>C (p.Tyr154His) was found as a homozygous occurrence in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PM3 Points= 1*0.5=0.5) (PMID:16256386)
PM3 points awarded in total: 1.5 ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1359,NM_000277.2(PAH):c.694C>T (p.Gln232Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-31,PM3,met,PubMed:30050108,"Patient genotype: c.442-1G>A (VarID594, P)/p.Q232*",Detected with known pathogenic variant c.442-1G>A  (PMID: 30050108),"Detected with known pathogenic variant c.442-1G>A  (PMID: 30050108) Patient genotype: c.442-1G>A (VarID594, P)/p.Q232*",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1681,NM_000277.1(PAH):c.716G>T (p.Gly239Val),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-23,PM3,met,PubMed:32106880,,detected with p.R408W (P 14 submitters) PMID: 31623983 IVS10–11g>a (P 7 submitters) PMID: 32106880 parental analysis not reported,detected with p.R408W (P 14 submitters) PMID: 31623983 IVS10–11g>a (P 7 submitters) PMID: 32106880 parental analysis not reported ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5673,NM_001354304.1:c.478C>T,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-10-15,PM3,met,PubMed:26322415,Patient genotype: p.R241C;Q160*. All mutations identified in patients were confirmed by analyzing parental DNA.,Detected in trans with p.R241C (pathogenic in ClinVar),Detected in trans with p.R241C (pathogenic in ClinVar) Patient genotype: p.R241C;Q160*. All mutations identified in patients were confirmed by analyzing parental DNA.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5919,NM_000277.3:c.353-2A>T,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PM3,met,PubMed:26322415,"c.[353-2A>T ];[331C>T ], p.[(?)];[R111*]. All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.",detected in trans with p.R111*  PMID: 26322415,"detected in trans with p.R111*  PMID: 26322415 c.[353-2A>T ];[331C>T ], p.[(?)];[R111*]. All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
670,NM_000277.2(PAH):c.493G>A (p.Ala165Thr),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-07,PP1,met,PubMed:26666653,c.493G>A]; [493G>A] genotype was observed in two cPKU siblings. The one tested between 3 and 10 years of age showed no decrease in Phe concentration (H0 384 μmol/L) while the one tested in the neonatal period showed a 36% decrease (H0 1680 μmol/L) but is not currently under BH4 treatment.,c.493G>A;493G>A genotype was observed in two cPKU siblings  PMID: 26666653,c.493G>A;493G>A genotype was observed in two cPKU siblings  PMID: 26666653 c.493G>A]; [493G>A] genotype was observed in two cPKU siblings. The one tested between 3 and 10 years of age showed no decrease in Phe concentration (H0 384 μmol/L) while the one tested in the neonatal period showed a 36% decrease (H0 1680 μmol/L) but is not currently under BH4 treatment.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
183,NM_000257.3(MYH7):c.2717A>G (p.Asp906Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
184,NM_000257.3(MYH7):c.2681A>G (p.Glu894Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
186,NM_000257.3(MYH7):c.2609G>A (p.Arg870His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
189,NM_000257.3(MYH7):c.2513C>T (p.Pro838Leu),MYH7,restrictive cardiomyopathy,MONDO:0005201,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
190,NM_000257.3(MYH7):c.2360G>A (p.Arg787His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Likely Benign,Autosomal dominant inheritance,Cardiomyopathy,2021-06-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
191,NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
192,NM_000257.3(MYH7):c.2221G>C (p.Gly741Arg),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
193,NM_000257.3(MYH7):c.2207T>C (p.Ile736Thr),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
194,NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
195,NM_000257.3(MYH7):c.2167C>G (p.Arg723Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
244,NM_000257.3(MYH7):c.2156G>A (p.Arg719Gln),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
245,NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
247,NM_000257.3(MYH7):c.2146G>A (p.Gly716Arg),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
248,NM_000257.3(MYH7):c.1988G>A (p.Arg663His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
249,NM_000257.3(MYH7):c.1750G>C (p.Gly584Arg),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
253,NM_000257.3(MYH7):c.1208G>A (p.Arg403Gln),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
255,NM_000257.3(MYH7):c.1358G>A (p.Arg453His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Head domain (aa 181-937),Head domain (aa 181-937),Head domain (aa 181-937) Head domain (aa 181-937),ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
2709,NM_000257.4(MYH7):c.2602G>C (p.Ala868Pro),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Likely Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2021-10-01,PM1,met,PubMed:27532257,mutation hotspot in between amino acids 181-937 in MYH7,Missense variants between amino acids 181-937 PMID: 27532257,Missense variants between amino acids 181-937 PMID: 27532257 mutation hotspot in between amino acids 181-937 in MYH7,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
178,NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2021-12-09,PS4,met,PubMed:27532257,Variant identified in probands with HCM,"SUMMARY: This variant has been reported in >35 individuals with hypertrophic cardiomyopathy, and a large proportion are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). 

Kärkkäinen 2004 (PMID:15556047) - 1 family with a proband with HCM->DCM and segregated in 5 relatives with HCM
Jääskeläinen 2014 (PMID:24888384) - 17 probands with HCM
Walsh 2017 (PMID:27532257) - 6 probands with HCM from OMGL data
LMM Data - 1 proband with HCM
SHaRe - 2 probands with HCM (lab not specified, may overlap with other sources)
Invitae - 5 probands with HCM
Ambry - 2 probands with HCM
GeneDx - 4 probands with HCM
OMGL - 10 probands with HCM (only considering 4 additional from Walsh paper), 13 segregations from 6 families

Literature from ClinVar, HGMD, and Google Scholar from Alamut search string","SUMMARY: This variant has been reported in >35 individuals with hypertrophic cardiomyopathy, and a large proportion are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). 

Kärkkäinen 2004 (PMID:15556047) - 1 family with a proband with HCM->DCM and segregated in 5 relatives with HCM
Jääskeläinen 2014 (PMID:24888384) - 17 probands with HCM
Walsh 2017 (PMID:27532257) - 6 probands with HCM from OMGL data
LMM Data - 1 proband with HCM
SHaRe - 2 probands with HCM (lab not specified, may overlap with other sources)
Invitae - 5 probands with HCM
Ambry - 2 probands with HCM
GeneDx - 4 probands with HCM
OMGL - 10 probands with HCM (only considering 4 additional from Walsh paper), 13 segregations from 6 families

Literature from ClinVar, HGMD, and Google Scholar from Alamut search string Variant identified in probands with HCM",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
182,NM_000257.3(MYH7):c.2722C>G (p.Leu908Val),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 5 probands with HCM,>20 probands with HCM including ClinVar SCV000059471.5; ClinVar SCV000692499.1; SHaRe data,>20 probands with HCM including ClinVar SCV000059471.5; ClinVar SCV000692499.1; SHaRe data Variant identified in 5 probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
183,NM_000257.3(MYH7):c.2717A>G (p.Asp906Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 7 probands with HCM,Variant identified in >20 probands with HCM including ClinVar SCV000059468.5,Variant identified in >20 probands with HCM including ClinVar SCV000059468.5 Variant identified in 7 probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
184,NM_000257.3(MYH7):c.2681A>G (p.Glu894Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,7 probands with HCM identified,">20 HCM probands including SHaRe, ClinVar SCV000059463.5; ClinVar SCV000212641.2; ClinVar SCV000253683.5)",">20 HCM probands including SHaRe, ClinVar SCV000059463.5; ClinVar SCV000212641.2; ClinVar SCV000253683.5) 7 probands with HCM identified",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
186,NM_000257.3(MYH7):c.2609G>A (p.Arg870His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 13 probands with HCM,>20 probands with HCM including ClinVar SCV000059458.5 and SHaRe data,>20 probands with HCM including ClinVar SCV000059458.5 and SHaRe data Variant identified in 13 probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
191,NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant found in probands with HCM,>15 probands including ClinVar SCV000203910.4 and ClinVar SCV000212638.1,>15 probands including ClinVar SCV000203910.4 and ClinVar SCV000212638.1 Variant found in probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
193,NM_000257.3(MYH7):c.2207T>C (p.Ile736Thr),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 6 probands with HCM,>20 probands with HCM including SHaRe data; ClinVar SCV000199207.4; ClinVar SCV000212631.2,>20 probands with HCM including SHaRe data; ClinVar SCV000199207.4; ClinVar SCV000212631.2 Variant identified in 6 probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
194,NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 4 probands with HCM,Variant identified in >20 probands with HCM (including ClinVar SCV000059423.5 and ClinVar SCV000212630.1),Variant identified in >20 probands with HCM (including ClinVar SCV000059423.5 and ClinVar SCV000212630.1) Variant identified in 4 probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
195,NM_000257.3(MYH7):c.2167C>G (p.Arg723Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 1 proband with HCM,12 proband with HCM including ClinVar SCV000059422.5 and SHaRe data,12 proband with HCM including ClinVar SCV000059422.5 and SHaRe data Variant identified in 1 proband with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
245,NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 4 probands with HCM,>20 probands with HCM (icluding SHaRe data and ClinVar SCV000059419.5),>20 probands with HCM (icluding SHaRe data and ClinVar SCV000059419.5) Variant identified in 4 probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
248,NM_000257.3(MYH7):c.1988G>A (p.Arg663His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in cases with HCM,>30 probands with HCM (including ClinVar SCV000212629.1; ClinVar SCV000219103.7; ClinVar SCV000059409.5; SHaRe data),>30 probands with HCM (including ClinVar SCV000212629.1; ClinVar SCV000219103.7; ClinVar SCV000059409.5; SHaRe data) Variant identified in cases with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
253,NM_000257.3(MYH7):c.1208G>A (p.Arg403Gln),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 4 probands with HCM,>25 probands with HCM (including data from: ClinVar SCV000692503.1; ClinVar SCV000253815.4; ClinVar SCV000059359.5; SHaRe data),>25 probands with HCM (including data from: ClinVar SCV000692503.1; ClinVar SCV000253815.4; ClinVar SCV000059359.5; SHaRe data) Variant identified in 4 probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
255,NM_000257.3(MYH7):c.1358G>A (p.Arg453His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:22429680,Variant identified in proband with HCM. Proband also carried Q882E variant in MYH7,">12 probands with HCM including ClinVar SCV000059369.5, ClinVar SCV000253816.4, SHaRe data",">12 probands with HCM including ClinVar SCV000059369.5, ClinVar SCV000253816.4, SHaRe data Variant identified in proband with HCM. Proband also carried Q882E variant in MYH7",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
199,NM_000257.3(MYH7):c.2358G>T (p.Thr786=),MYH7,cardiomyopathy,MONDO:0004994,Benign,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,BA1,met,PubMed:29300372,BA1 applied,The filtering allele frequency of the c.2358G>T (p.Thr786=) variant in the MYH7 gene is 0.15% (33/16512) of South Asian chromosomes by the Exome Aggregation Consortium,The filtering allele frequency of the c.2358G>T (p.Thr786=) variant in the MYH7 gene is 0.15% (33/16512) of South Asian chromosomes by the Exome Aggregation Consortium BA1 applied,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
311,NM_002880.3(RAF1):c.775T>A (p.Ser259Thr),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-04-13,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).,"The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
312,NM_002880.3(RAF1):c.788T>G (p.Val263Gly),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-07-01,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).,"The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
322,NM_002834.4(PTPN11):c.781C>T (p.Leu261Phe),PTPN11,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
328,NM_002834.4(PTPN11):c.794G>A (p.Arg265Gln),PTPN11,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
348,NM_005343.3(HRAS):c.175G>A (p.Ala59Thr),HRAS,RASopathy,MONDO:0009026,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2024-10-02,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581).","The variant is in a location (amino acids 57 – 64), that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of HRAS (PM1)","The variant is in a location (amino acids 57 – 64), that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of HRAS (PM1) Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.3.0_version=2.3.0.csv
353,NM_004333.4(BRAF):c.1785T>G (p.Phe595Leu),BRAF,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581, 16439621).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
374,NM_005633.3(SOS1):c.1642A>C (p.Ser548Arg),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
377,NM_005633.3(SOS1):c.508A>G (p.Lys170Glu),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581)","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581)","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581) Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581)",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
378,NM_002880.3(RAF1):c.770C>T (p.Ser257Leu),RAF1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
728,NM_002834.4(PTPN11):c.1403C>T (p.Thr468Met),PTPN11,Noonan syndrome with multiple lentigines,MONDO:0007893,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-07-15,PM1,met,PubMed:29493581,ClinGen RAS EP decided this AA is located in a hotspot,The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11  (PM1; PMID 29493581).,The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11  (PM1; PMID 29493581). ClinGen RAS EP decided this AA is located in a hotspot,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1215,NM_002834.4(PTPN11):c.215C>T (p.Ala72Val),PTPN11,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-03-25,PM1,met,PubMed:29493581,RAS VCEP outlines hotspot regions,"Directly interacting residues between N-SH2 and PTPN domains: 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284 (Gelb et al. 2018).","Directly interacting residues between N-SH2 and PTPN domains: 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284 (Gelb et al. 2018). RAS VCEP outlines hotspot regions",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1530,NM_005633.3(SOS1):c.1276C>A (p.Gln426Lys),SOS1,RASopathy,MONDO:0021060,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2020-07-27,PM1,met,PubMed:29493581,,The RASopathy EP has defined amino acids 420-500 of SOS1 to be a region supporting pathogenicity.,The RASopathy EP has defined amino acids 420-500 of SOS1 to be a region supporting pathogenicity. ,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
392,NM_002755.3(MAP2K1):c.389A>G (p.Tyr130Cys),MAP2K1,cardiofaciocutaneous syndrome,MONDO:0015280,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PS3,met,PubMed:23093928,"In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815).","In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815).","In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
400,NM_004333.4(BRAF):c.770A>G (p.Gln257Arg),BRAF,cardiofaciocutaneous syndrome,MONDO:0015280,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PS3,met,PubMed:19376813,Phosphorylation of myelin basic protein in a coupled MEK/ERK2 kinase assay,, Phosphorylation of myelin basic protein in a coupled MEK/ERK2 kinase assay,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
728,NM_002834.4(PTPN11):c.1403C>T (p.Thr468Met),PTPN11,Noonan syndrome with multiple lentigines,MONDO:0007893,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-07-15,PS3,met,PubMed:24935154,Mutant exhibited reduced catalytic activity,"In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586).","In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586). Mutant exhibited reduced catalytic activity",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
729,NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys),PTPN11,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2024-10-01,PS3,met,PubMed:22711529,Functional characterization identifies that the p.Tyr63Cys variant perturb the stability of the N-SH2/PTP interaction required to maintain SHP2 in its catalytically inactive conformation.,In vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529).,In vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). Functional characterization identifies that the p.Tyr63Cys variant perturb the stability of the N-SH2/PTP interaction required to maintain SHP2 in its catalytically inactive conformation.,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.3.0_version=2.3.0.csv
1197,NM_002834.4(PTPN11):c.184T>G (p.Tyr62Asp),PTPN11,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-02-18,PS3,met,PubMed:22711529,“Under basal conditions the NS-causing SHP2Asp62 that showed a 2.3-fold increase in substrate dephosphorylation”,, “Under basal conditions the NS-causing SHP2Asp62 that showed a 2.3-fold increase in substrate dephosphorylation”,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1580,NM_005633.3(SOS1):c.1656G>C (p.Arg552Ser),SOS1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PS3,met,PubMed:27304678,Transfected wild-type and mutant SOS1 constructs into HEK293T cells and measured the effect on basal levels of phosphorylated ERK1/2. Found that the p.R552S variant significantly increased p-ERK signaling relative to WT (p = 0.0039). This meets criteria for PS3.,variant increased p-ERK signaling (PMID 27304678),variant increased p-ERK signaling (PMID 27304678) Transfected wild-type and mutant SOS1 constructs into HEK293T cells and measured the effect on basal levels of phosphorylated ERK1/2. Found that the p.R552S variant significantly increased p-ERK signaling relative to WT (p = 0.0039). This meets criteria for PS3.,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
729,NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys),PTPN11,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2024-10-01,PS4,met,PubMed:24219368,1 proband with Noonan syndrome and a mature cataract,6 probands have been identified with NS/ NSML; this code was not applied in the Gelb 2018 paper,6 probands have been identified with NS/ NSML; this code was not applied in the Gelb 2018 paper 1 proband with Noonan syndrome and a mature cataract,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.3.0_version=2.3.0.csv
1237,NM_002834.4(PTPN11):c.782T>A (p.Leu261His),PTPN11,RASopathy,MONDO:0021060,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2020-03-24,PS4,met,PubMed:22253195,,"This variant was observed in 7 probands with Noonan syndrome (PMID: 28074573, 22253195, 23756559).","This variant was observed in 7 probands with Noonan syndrome (PMID: 28074573, 22253195, 23756559). ",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1237,NM_002834.4(PTPN11):c.782T>A (p.Leu261His),PTPN11,RASopathy,MONDO:0021060,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2020-03-24,PS4,met,PubMed:23756559,,"This variant was observed in 7 probands with Noonan syndrome (PMID: 28074573, 22253195, 23756559).","This variant was observed in 7 probands with Noonan syndrome (PMID: 28074573, 22253195, 23756559). ",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1580,NM_005633.3(SOS1):c.1656G>C (p.Arg552Ser),SOS1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PS4,met,PubMed:21387466,"Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. This was a large study of patients with clinical features of a RASopathy that has been described elsewhere. This study describes c.1656G>C (p.Arg552Ser) in 2 sporadic, 7 fam unknown cases","This variant was reported in at least 7 patients with clinical features of NS (PMID: 26297936, 25862627, 17143282, 21387466, 19020799, 23885229, 22190897, 19352411)","This variant was reported in at least 7 patients with clinical features of NS (PMID: 26297936, 25862627, 17143282, 21387466, 19020799, 23885229, 22190897, 19352411) Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. This was a large study of patients with clinical features of a RASopathy that has been described elsewhere. This study describes c.1656G>C (p.Arg552Ser) in 2 sporadic, 7 fam unknown cases",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1583,NM_005633.3(SOS1):c.1655G>A (p.Arg552Lys),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PS4,met,PubMed:21387466,"Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, 
 (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. The variant was identified in 2 sporadic cases with NS and 2 ""fam.unknown"" cases in this study.","Kilinc et al. 2014: Variant was detected 12 year old boy with tooth anomalies, low set ears, bilateral proptosis, sparse eyebrows, epicanthal folds, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, webbed neck, low posterior hairline, pectus excavatum, cubitus valgus, non palpable left testicle, myopia, scoliosis, diagnossi considered NS.

Partners LMM: The variant has been identified in 6 affected patients with NS at this lab. Inheritance is unknown for these individuals.

GeneDx:","Kilinc et al. 2014: Variant was detected 12 year old boy with tooth anomalies, low set ears, bilateral proptosis, sparse eyebrows, epicanthal folds, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, webbed neck, low posterior hairline, pectus excavatum, cubitus valgus, non palpable left testicle, myopia, scoliosis, diagnossi considered NS.

Partners LMM: The variant has been identified in 6 affected patients with NS at this lab. Inheritance is unknown for these individuals.

GeneDx: Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, 
 (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. The variant was identified in 2 sporadic cases with NS and 2 ""fam.unknown"" cases in this study.",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1583,NM_005633.3(SOS1):c.1655G>A (p.Arg552Lys),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PS4,met,PubMed:30266093,Patient 133-PRE is a prenatal patient with an AD/de novo heterozygous variant. The phenotypic information for this fetus was not recorded and therefore the clinical suspicion for NS cannot be used for PS4 or PM6/PS2,"Kilinc et al. 2014: Variant was detected 12 year old boy with tooth anomalies, low set ears, bilateral proptosis, sparse eyebrows, epicanthal folds, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, webbed neck, low posterior hairline, pectus excavatum, cubitus valgus, non palpable left testicle, myopia, scoliosis, diagnossi considered NS.

Partners LMM: The variant has been identified in 6 affected patients with NS at this lab. Inheritance is unknown for these individuals.

GeneDx:","Kilinc et al. 2014: Variant was detected 12 year old boy with tooth anomalies, low set ears, bilateral proptosis, sparse eyebrows, epicanthal folds, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, webbed neck, low posterior hairline, pectus excavatum, cubitus valgus, non palpable left testicle, myopia, scoliosis, diagnossi considered NS.

Partners LMM: The variant has been identified in 6 affected patients with NS at this lab. Inheritance is unknown for these individuals.

GeneDx: Patient 133-PRE is a prenatal patient with an AD/de novo heterozygous variant. The phenotypic information for this fetus was not recorded and therefore the clinical suspicion for NS cannot be used for PS4 or PM6/PS2",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
377,NM_005633.3(SOS1):c.508A>G (p.Lys170Glu),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM6,met,PubMed:21387466,"The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466)","The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466)","The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466) The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466)",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
960,NM_005633.3(SOS1):c.2673+14T>C,SOS1,RASopathy,MONDO:0021060,Benign,Autosomal dominant inheritance,RASopathy,2019-10-02,BP5,met,PubMed:21387466,"Identified as a disease-unrelated SOS1 sequence variant in a patient. The RASopathy phenotype was not specified for the individual, but patients in the study had NS, CFCS, and CHDs.","2 patients from LMM internal data had pathogenic variants in other genes (SHOC2:c.4A>G, classified as Path by RAS VCEP; PTPN11:c.179G>C, classified as Path by 5 submitters and well-studied in lit). Also observed by Lepri et al.","2 patients from LMM internal data had pathogenic variants in other genes (SHOC2:c.4A>G, classified as Path by RAS VCEP; PTPN11:c.179G>C, classified as Path by 5 submitters and well-studied in lit). Also observed by Lepri et al. Identified as a disease-unrelated SOS1 sequence variant in a patient. The RASopathy phenotype was not specified for the individual, but patients in the study had NS, CFCS, and CHDs.",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
124,NM_000314.6(PTEN):c.395G>A (p.Gly132Asp),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2021-10-29,PS3,met,PubMed:32350270,LOF for multiple assays c/w Mighell results,, LOF for multiple assays c/w Mighell results,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
545,NM_000314.6(PTEN):c.331T>C (p.Trp111Arg),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2022-09-30,PS3,met,PubMed:29785012,"Protein abundance score 0.09, ""low"" abundance category.",," Protein abundance score 0.09, ""low"" abundance category.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
546,NM_000314.6(PTEN):c.392C>T (p.Thr131Ile),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2018-12-10,PS3,met,PubMed:29785012,"Variant categorized as ""WT-like"" on VAMPseq high throughput assay assessing protein abundance as a measure of stability.",," Variant categorized as ""WT-like"" on VAMPseq high throughput assay assessing protein abundance as a measure of stability.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
747,NM_000314.6(PTEN):c.370T>C (p.Cys124Arg),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:29785012,"Appears to show decreased stability (score 0.28) but EP still figuring out cutoff for this publication, and PS3 already applied for other literature.",I agree (FH),"I agree (FH) Appears to show decreased stability (score 0.28) but EP still figuring out cutoff for this publication, and PS3 already applied for other literature.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
749,NM_000314.6(PTEN):c.388C>G (p.Arg130Gly),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:29785012,Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198.,"Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees.","Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees. Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
749,NM_000314.6(PTEN):c.388C>G (p.Arg130Gly),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:19457929,Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.,"Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees.","Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees. Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
749,NM_000314.6(PTEN):c.388C>G (p.Arg130Gly),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:20926450,"He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.","Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees.","Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees. He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
750,NM_000314.6(PTEN):c.477G>T (p.Arg159Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:29617666,"Article studied variant for splicing impact.  Identified in TCGA tumor; RT-PCR showed 21bp deletion.  However, fig. 5 mini-gene appears same as WT?  No apparent impact on native site, but possible strengthening of alternative SDS.",," Article studied variant for splicing impact.  Identified in TCGA tumor; RT-PCR showed 21bp deletion.  However, fig. 5 mini-gene appears same as WT?  No apparent impact on native site, but possible strengthening of alternative SDS.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
757,NM_000314.6(PTEN):c.634+5G>C,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2023-12-18,PS3,met,PubMed:28677221,Variant shown to cause exon 6 skipping in pt cells.,RNA assay shows impact on splicing. Variant shown to cause exon 6 skipping in pt cells (PMID: 28677221).,RNA assay shows impact on splicing. Variant shown to cause exon 6 skipping in pt cells (PMID: 28677221). Variant shown to cause exon 6 skipping in pt cells.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1048,NM_000314.7(PTEN):c.464A>G (p.Tyr155Cys),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-12-11,PS3,met,PubMed:27829222,Phadngam S et al. evaluated ovarian cancer cells and PTEN protein expression.  Figure 4C shows a theoretical 3D structure of Y155C and concluded that the presence of this mutation does not alter the structure of PTEN including the phosphatase domain (*discuss with group whether this is negates criteria).,"Miguell et al. table shows G score of -2.26881194 which is in the truncation-like range 
(< -2.13). Han et al. paper demonstrated variant as having no phosphatase activity compared to WT in Figure 2G.  Rodriguez-Escudero et al completed a functional assessment of PTEN mutations related to PHTS.  They demonstrated  in Figure 6A that this variant had PIP3 (+) cells with activity of 100% which was similar to the vector activity.  WT showed negligible activity.  Phadngam S et al. evaluated ovarian cancer cells and PTEN protein expression.  Figure 4C shows a theoretical 3D structure of Y155C and concluded that the presence of this mutation does not alter the structure of PTEN including the phosphatase domain (*discuss with group whether this is negates criteria). Smith et al. evaluated mutational effects that lead to PTEN-ASD and PTEN-cancer phenotypes.  Using protein-dynamic structural-network analysis.  They assessed the difference in closeness centrality at the network level and identified significant differences compared to WT (figures S5A and S5B). This variant is found in the central core of the protein. *Discuss figure 3 (residue-based betweenness centrality estimation plot) with group. Andres-Pons et al. identified a patient described to meet criteria of PHTS/Cowden with this variant. Yeast functional analysis (table 1) was conducted on this variant and found no reconstitution and low yeast protein expression level.  Clinical features of patient could not be located in this paper or referenced papers by the authors.","Miguell et al. table shows G score of -2.26881194 which is in the truncation-like range 
(< -2.13). Han et al. paper demonstrated variant as having no phosphatase activity compared to WT in Figure 2G.  Rodriguez-Escudero et al completed a functional assessment of PTEN mutations related to PHTS.  They demonstrated  in Figure 6A that this variant had PIP3 (+) cells with activity of 100% which was similar to the vector activity.  WT showed negligible activity.  Phadngam S et al. evaluated ovarian cancer cells and PTEN protein expression.  Figure 4C shows a theoretical 3D structure of Y155C and concluded that the presence of this mutation does not alter the structure of PTEN including the phosphatase domain (*discuss with group whether this is negates criteria). Smith et al. evaluated mutational effects that lead to PTEN-ASD and PTEN-cancer phenotypes.  Using protein-dynamic structural-network analysis.  They assessed the difference in closeness centrality at the network level and identified significant differences compared to WT (figures S5A and S5B). This variant is found in the central core of the protein. *Discuss figure 3 (residue-based betweenness centrality estimation plot) with group. Andres-Pons et al. identified a patient described to meet criteria of PHTS/Cowden with this variant. Yeast functional analysis (table 1) was conducted on this variant and found no reconstitution and low yeast protein expression level.  Clinical features of patient could not be located in this paper or referenced papers by the authors. Phadngam S et al. evaluated ovarian cancer cells and PTEN protein expression.  Figure 4C shows a theoretical 3D structure of Y155C and concluded that the presence of this mutation does not alter the structure of PTEN including the phosphatase domain (*discuss with group whether this is negates criteria).",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
88,NM_000314.6(PTEN):c.1171C>T (p.Pro391Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2020-03-26,BS3,met,PubMed:30993208,phosphorylated AKT and subcellular localization similar to WT,"Phosphatase activity, stability, pAKT, and subcellular localization similar to WT","Phosphatase activity, stability, pAKT, and subcellular localization similar to WT phosphorylated AKT and subcellular localization similar to WT",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
557,NM_000314.6(PTEN):c.79+7A>G,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Benign,Autosomal dominant inheritance,PTEN,2023-10-19,BS3,met,PubMed:28677221,"Variant reported to not demonstrate splicing impact, but results not shown.","Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (Chen HJ et al. 2017 PMID: 28677221 showed c.79+7A>G had no demonstrated splicing impact)","Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (Chen HJ et al. 2017 PMID: 28677221 showed c.79+7A>G had no demonstrated splicing impact) Variant reported to not demonstrate splicing impact, but results not shown.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
764,NM_000314.6(PTEN):c.210-7_210-3del5,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Benign,Autosomal dominant inheritance,PTEN,2019-07-23,BS3,met,PubMed:28677221,No splicing effect by mRNA testing (pt lymphoblast-derived cell lines were used).,Chen 2017,Chen 2017 No splicing effect by mRNA testing (pt lymphoblast-derived cell lines were used).,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
777,NM_000314.6(PTEN):c.364A>G (p.Ile122Val),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2022-09-30,BS3,met,PubMed:29785012,Variant demonstrated WT-like abundance on high-throughput VAMPseq assay.,"PMID 21828076: demonstrated that missense change does not affect PTEN PIP3 phosphatase activity.

I agree (FH)","PMID 21828076: demonstrated that missense change does not affect PTEN PIP3 phosphatase activity.

I agree (FH) Variant demonstrated WT-like abundance on high-throughput VAMPseq assay.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1473,NM_000314.7(PTEN):c.210-39A>G,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Benign,Autosomal dominant inheritance,PTEN,2020-06-18,BS3,met,PubMed:28677221,"Authors characterized PTEN mRNA processing, analyzed PTEN expression, and downstream readouts of P-AKT and P-ERK1/2. RNA for our variant showed no change.",RNA for our variant showed no change (PMID 28677221).,"RNA for our variant showed no change (PMID 28677221). Authors characterized PTEN mRNA processing, analyzed PTEN expression, and downstream readouts of P-AKT and P-ERK1/2. RNA for our variant showed no change.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
124,NM_000314.6(PTEN):c.395G>A (p.Gly132Asp),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2021-10-29,PS4,met,PubMed:25288137,4yo M with autism and OFC +5.9SD. Peds score = 5 = 1 phenotype specificity point.,"2.5 phenotype specificity points from literature, additional 1.5 points from internal laboratory case.","2.5 phenotype specificity points from literature, additional 1.5 points from internal laboratory case. 4yo M with autism and OFC +5.9SD. Peds score = 5 = 1 phenotype specificity point.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
759,NM_000314.6(PTEN):c.320A>T (p.Asp107Val),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PP1,met,PubMed:23886400,"Variant identified in proband described in PS4 section, variant also present in his daughter with hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis. 1 meiosis.","3 meioses total (1 Paparo, 1 Hansen-Kiss, 1 GDx internal family)","3 meioses total (1 Paparo, 1 Hansen-Kiss, 1 GDx internal family) Variant identified in proband described in PS4 section, variant also present in his daughter with hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis. 1 meiosis.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
759,NM_000314.6(PTEN):c.320A>T (p.Asp107Val),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PM6,met,PubMed:25418537,,"Variant occurred de novo in a child in the autism simplex cohort; methods appear to have been targeted to known candidate genes, not exome-based, but paper notes ""paternity firmly established"" via other variant info. May review with team to see whether would wish to apply PM6 or PS2. KS: Agrees and suggests applying PM6.","Variant occurred de novo in a child in the autism simplex cohort; methods appear to have been targeted to known candidate genes, not exome-based, but paper notes ""paternity firmly established"" via other variant info. May review with team to see whether would wish to apply PM6 or PS2. KS: Agrees and suggests applying PM6. ",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1189,NM_000152.4(GAA):c.1687C>T (p.Gln563Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3,met,PubMed:25741864,,"This variant was found in compound heterozygosity with a unique pathogenic variant in GAA, c.722_723delTT, in one patient with Pompe disease who also meets the ClinGen LSD VCEP's PP4 specifications. The phase was confirmed as in trans. Based on the ClinGen LSD VCEP's guidelines, this data was given a total of 1 point, which meets PM3.","This variant was found in compound heterozygosity with a unique pathogenic variant in GAA, c.722_723delTT, in one patient with Pompe disease who also meets the ClinGen LSD VCEP's PP4 specifications. The phase was confirmed as in trans. Based on the ClinGen LSD VCEP's guidelines, this data was given a total of 1 point, which meets PM3. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1323,NM_000152.4(GAA):c.2662G>T (p.Glu888Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-27,PM3,met,PubMed:27417441,,"At least 6 patients have been reported with this variant and deficiency of GAA activity meeting the ClinGen LSD VCEP’s PP4 specifications. One of these individuals is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16531044; 0.5 points), and another is homozygous for the variant (PMID 17723315; 0.5 points). A total of one point was given, meeting PM3. Other individuals meeting PP4 specifications are compound heterozygous for the variant and either c.1574T>A (p.Phe525Tyr) (PMID 21232767), c.1935C>A (p.Asp645Glu) (PMID 18458862), or c.2238G>C (p.Trp746Cys) (PMID 25526786). However in each case, the in trans data from these patients will be used in the assessment of the other variant and was not used here in order to avoid a circular argument. Additional cases with the variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 24269976, 25455803, 25626711, 27417441, 28394184, 31743840), or the patient carried a pseudodeficiency allele (PMID 21232767).","At least 6 patients have been reported with this variant and deficiency of GAA activity meeting the ClinGen LSD VCEP’s PP4 specifications. One of these individuals is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16531044; 0.5 points), and another is homozygous for the variant (PMID 17723315; 0.5 points). A total of one point was given, meeting PM3. Other individuals meeting PP4 specifications are compound heterozygous for the variant and either c.1574T>A (p.Phe525Tyr) (PMID 21232767), c.1935C>A (p.Asp645Glu) (PMID 18458862), or c.2238G>C (p.Trp746Cys) (PMID 25526786). However in each case, the in trans data from these patients will be used in the assessment of the other variant and was not used here in order to avoid a circular argument. Additional cases with the variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 24269976, 25455803, 25626711, 27417441, 28394184, 31743840), or the patient carried a pseudodeficiency allele (PMID 21232767). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1356,NM_000152.4(GAA):c.1438-1G>C,GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3,met,PubMed:27896092,,"Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254)(0.5 points). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G. The phase is unknown (0.5 points). A total of 1 point was given, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340).","Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254)(0.5 points). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G. The phase is unknown (0.5 points). A total of 1 point was given, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1356,NM_000152.4(GAA):c.1438-1G>C,GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3,met,PubMed:24495340,,"Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254)(0.5 points). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G. The phase is unknown (0.5 points). A total of 1 point was given, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340).","Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254)(0.5 points). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G. The phase is unknown (0.5 points). A total of 1 point was given, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1584,NM_000152.4(GAA):c.1128_1129delGGinsC (p.Trp376Cysfs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3,met,PubMed:27408821,"c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, -32-13T>G (a known pathogenic variant), in an individual with late onset Pompe disease. The phase is unknown. No GAA activity data is available, and therefore this data will not be included.","Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID: 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID  26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768).","Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID: 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID  26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768). c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, -32-13T>G (a known pathogenic variant), in an individual with late onset Pompe disease. The phase is unknown. No GAA activity data is available, and therefore this data will not be included.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1584,NM_000152.4(GAA):c.1128_1129delGGinsC (p.Trp376Cysfs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3,met,PubMed:29523196,"c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, -32-13T>G, in an individual with late onset Pompe disease. The phase is unknown. No GAA activity data is available,and therefore this data will not be included. The patient is on ERT.","Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID: 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID  26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768).","Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID: 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID  26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768). c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, -32-13T>G, in an individual with late onset Pompe disease. The phase is unknown. No GAA activity data is available,and therefore this data will not be included. The patient is on ERT.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1585,NM_000152.4(GAA):c.1841C>A (p.Thr614Lys),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3,met,PubMed:30564623,"Patient AOP13, with a prior clinical diagnosis of limb girdle muscular dystrophy, is compound heterozygous for c.1841C>A (p.Thr614Lys) and c.-32-13T>G. No individual GAA activity is provided, therefore this data will not be included.","The variant was found in compound heterozygosity in two patients published in the literature who meet the specifications for PP4. In one patient, the variant is in compound heterozygosity with c.1076–22T>G, phase unknown (PMID 21484825) (in trans data will be used for classification of c.1076–22T>G and is therefore not used here in order to avoid a circular argument), and in the other patient, the variant is in compound heterozygosity with c.-32-13T>G, phase unknown (PMID 24590251) (0.5 points). In addition, in a clinical laboratory, the variant was found in two patients with c.-32-13T>G (not counted because another patient with the same genotype, phase unknown, has already been included), one patient with c.2481+102_2646+31del (0.5 points), and one patient with c.1402A>T (p.Ile468Phe) (in trans data will be used for classification of p.Ile468Phe and is therefore not used here in order to avoid a circular argument), with all patients meeting PP4_Moderate and phase unknown. This data was given a total of 1 point, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 25544546, 27708273, 30564623).","The variant was found in compound heterozygosity in two patients published in the literature who meet the specifications for PP4. In one patient, the variant is in compound heterozygosity with c.1076–22T>G, phase unknown (PMID 21484825) (in trans data will be used for classification of c.1076–22T>G and is therefore not used here in order to avoid a circular argument), and in the other patient, the variant is in compound heterozygosity with c.-32-13T>G, phase unknown (PMID 24590251) (0.5 points). In addition, in a clinical laboratory, the variant was found in two patients with c.-32-13T>G (not counted because another patient with the same genotype, phase unknown, has already been included), one patient with c.2481+102_2646+31del (0.5 points), and one patient with c.1402A>T (p.Ile468Phe) (in trans data will be used for classification of p.Ile468Phe and is therefore not used here in order to avoid a circular argument), with all patients meeting PP4_Moderate and phase unknown. This data was given a total of 1 point, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 25544546, 27708273, 30564623). Patient AOP13, with a prior clinical diagnosis of limb girdle muscular dystrophy, is compound heterozygous for c.1841C>A (p.Thr614Lys) and c.-32-13T>G. No individual GAA activity is provided, therefore this data will not be included.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1585,NM_000152.4(GAA):c.1841C>A (p.Thr614Lys),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3,met,PubMed:27708273,"Patient 1117 is compound heterozygous for c.1841C>A (p.Thr614Lys) and the known pathogenic variant, c.-32-13T>G identified by exome sequencing. The patient had a clinical diagnosis of limb girdle muscular dystrophy.","The variant was found in compound heterozygosity in two patients published in the literature who meet the specifications for PP4. In one patient, the variant is in compound heterozygosity with c.1076–22T>G, phase unknown (PMID 21484825) (in trans data will be used for classification of c.1076–22T>G and is therefore not used here in order to avoid a circular argument), and in the other patient, the variant is in compound heterozygosity with c.-32-13T>G, phase unknown (PMID 24590251) (0.5 points). In addition, in a clinical laboratory, the variant was found in two patients with c.-32-13T>G (not counted because another patient with the same genotype, phase unknown, has already been included), one patient with c.2481+102_2646+31del (0.5 points), and one patient with c.1402A>T (p.Ile468Phe) (in trans data will be used for classification of p.Ile468Phe and is therefore not used here in order to avoid a circular argument), with all patients meeting PP4_Moderate and phase unknown. This data was given a total of 1 point, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 25544546, 27708273, 30564623).","The variant was found in compound heterozygosity in two patients published in the literature who meet the specifications for PP4. In one patient, the variant is in compound heterozygosity with c.1076–22T>G, phase unknown (PMID 21484825) (in trans data will be used for classification of c.1076–22T>G and is therefore not used here in order to avoid a circular argument), and in the other patient, the variant is in compound heterozygosity with c.-32-13T>G, phase unknown (PMID 24590251) (0.5 points). In addition, in a clinical laboratory, the variant was found in two patients with c.-32-13T>G (not counted because another patient with the same genotype, phase unknown, has already been included), one patient with c.2481+102_2646+31del (0.5 points), and one patient with c.1402A>T (p.Ile468Phe) (in trans data will be used for classification of p.Ile468Phe and is therefore not used here in order to avoid a circular argument), with all patients meeting PP4_Moderate and phase unknown. This data was given a total of 1 point, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 25544546, 27708273, 30564623). Patient 1117 is compound heterozygous for c.1841C>A (p.Thr614Lys) and the known pathogenic variant, c.-32-13T>G identified by exome sequencing. The patient had a clinical diagnosis of limb girdle muscular dystrophy.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1705,NM_000152.5(GAA):c.236_246del (p.Pro79fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PM3,met,PubMed:23825616,,"This variant was found in compound heterozygosity with a unique pathogenic  variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications, with either c.377G>A (p.Trp126Ter), in trans (PMID 17056254), or c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1.5 points which meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626).","This variant was found in compound heterozygosity with a unique pathogenic  variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications, with either c.377G>A (p.Trp126Ter), in trans (PMID 17056254), or c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1.5 points which meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1718,NM_000152.5(GAA):c.482_483del (p.Pro161fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PM3,met,PubMed:32248831,,"Four individuals have been reported with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. Of these individuals, two are compound heterozygous for c.-32-13T>G (PMID 9196050; 0.5 points given for PM3), and one is compound heterozygous for c.-32-3C>A (PMID 21550241, probably the same patient is also reported in PMIDs 30155607, 21803581). The phase is unknown in these cases. The in trans data for the latter patient, who is compound heterozygous for c.-32-3C>A, will be used in the assessment of that variant and was not included here in order to avoid a circular argument. Therefore, a total of 0.5 points was given, meeting PM3_Supporting. Additional patients have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) or full HGVS nomenclature was not provided (PMIDs 11071489, 28648663, 32248831).","Four individuals have been reported with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. Of these individuals, two are compound heterozygous for c.-32-13T>G (PMID 9196050; 0.5 points given for PM3), and one is compound heterozygous for c.-32-3C>A (PMID 21550241, probably the same patient is also reported in PMIDs 30155607, 21803581). The phase is unknown in these cases. The in trans data for the latter patient, who is compound heterozygous for c.-32-3C>A, will be used in the assessment of that variant and was not included here in order to avoid a circular argument. Therefore, a total of 0.5 points was given, meeting PM3_Supporting. Additional patients have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) or full HGVS nomenclature was not provided (PMIDs 11071489, 28648663, 32248831). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1318,NM_000152.4(GAA):c.1051delG (p.Val351Cysfs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PP4,met,PubMed:22676651,Patient 4 has GAA activity in the affected range when compared to the laboratory’s control range.  GAA activity measured  in isolated lymphocytes with 4-methylumbelliferyl-α-D-glucopyranoside as substrate without acarbose was 0.01 nmole/mg/hr (normal range of 0.19-0.45 nmole/mg/hr),"Three individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 20033296, 20817528, 22676651). This meets the specifications for PP4.","Three individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 20033296, 20817528, 22676651). This meets the specifications for PP4. Patient 4 has GAA activity in the affected range when compared to the laboratory’s control range.  GAA activity measured  in isolated lymphocytes with 4-methylumbelliferyl-α-D-glucopyranoside as substrate without acarbose was 0.01 nmole/mg/hr (normal range of 0.19-0.45 nmole/mg/hr)",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1344,NM_000152.3(GAA):c.118C>T (p.Arg40Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PP4,met,PubMed:24107549,"Report of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three variants segregated in the family. One sibling, with a progressive undefined myopathy, was deceased. Seven siblings were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G>A [p.N882fs] in GAA. Six siblings with this genotype had muscle GAA activity ranging from 2.3-3.1 pmol/min/mg protein (normal range 34 – 138) (<10% the lower limit of normal) and one (II-4) had GAA activity of 4.2 pmol/min/mg protein). In dried blood spots, the value was 0.09-0.31 (normal 1.86-219 nmol/h/l) in 6 siblings and 4.2 in II-4.","Multiple individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 24107549, 22958975, 22676651). This data meets the ClinGen LSD VCEP's specifications for PP4.","Multiple individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 24107549, 22958975, 22676651). This data meets the ClinGen LSD VCEP's specifications for PP4. Report of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three variants segregated in the family. One sibling, with a progressive undefined myopathy, was deceased. Seven siblings were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G>A [p.N882fs] in GAA. Six siblings with this genotype had muscle GAA activity ranging from 2.3-3.1 pmol/min/mg protein (normal range 34 – 138) (<10% the lower limit of normal) and one (II-4) had GAA activity of 4.2 pmol/min/mg protein). In dried blood spots, the value was 0.09-0.31 (normal 1.86-219 nmol/h/l) in 6 siblings and 4.2 in II-4.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1344,NM_000152.3(GAA):c.118C>T (p.Arg40Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PP4,met,PubMed:22676651,Patient 12 is compound heterozygous for c.118C>T (p.Arg40Ter) and c.-32-13T>G. The phase of the variants is unknown. GAA activity in lymphocytes is 0.5 (normal range of 9-42 nmole/mg/hr). (0.5 points),"Multiple individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 24107549, 22958975, 22676651). This data meets the ClinGen LSD VCEP's specifications for PP4.","Multiple individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 24107549, 22958975, 22676651). This data meets the ClinGen LSD VCEP's specifications for PP4. Patient 12 is compound heterozygous for c.118C>T (p.Arg40Ter) and c.-32-13T>G. The phase of the variants is unknown. GAA activity in lymphocytes is 0.5 (normal range of 9-42 nmole/mg/hr). (0.5 points)",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1410,NM_000152.5(GAA):c.352C>T (p.Gln118Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-06-03,PP4,met,PubMed:31342611,,"This variant has been reported in a patient with <30% normal GAA activity in skin fibroblasts (PMID 22252923, personal communication), meeting PP4.","This variant has been reported in a patient with <30% normal GAA activity in skin fibroblasts (PMID 22252923, personal communication), meeting PP4. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1703,NM_000152.4(GAA):c.241C>T (p.Gln81Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PP4,met,PubMed:25526786,,"Three siblings with this variant have residual GAA activity in lymphocytes <10% of the normal mean (PMID 25526786). Note that in some other studies, c.2238G>C (p.Trp746Cys) has been found in cis with the pseudodeficiency variant, p.Gly576Ser. This pseudodeficiency variant was not reported in this study and hence PP4 is met.","Three siblings with this variant have residual GAA activity in lymphocytes <10% of the normal mean (PMID 25526786). Note that in some other studies, c.2238G>C (p.Trp746Cys) has been found in cis with the pseudodeficiency variant, p.Gly576Ser. This pseudodeficiency variant was not reported in this study and hence PP4 is met. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1705,NM_000152.5(GAA):c.236_246del (p.Pro79fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PP4,met,PubMed:30022036,,"Two  individuals have been reported with this variant and GAA activity in the affected range when compared to the laboratory’s control range (PMIDs 17056254, 30778879) . This meets the criteria for PP4.","Two  individuals have been reported with this variant and GAA activity in the affected range when compared to the laboratory’s control range (PMIDs 17056254, 30778879) . This meets the criteria for PP4. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1737,NM_000152.5(GAA):c.2214G>A (p.Trp738Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PP4,met,PubMed:22676651,,Twins have been reported with this variant and GAA activity in dried blood spots in the affected range in a clinically validated assay (PMID 26575883) and another patient has GAA activity in the affected range in lymphocytes (PMID 22676651). This meets the specifications for PP4.,Twins have been reported with this variant and GAA activity in dried blood spots in the affected range in a clinically validated assay (PMID 26575883) and another patient has GAA activity in the affected range in lymphocytes (PMID 22676651). This meets the specifications for PP4. ,ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
635,NM_004086.2(COCH):c.151C>T (p.Pro51Ser),COCH,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal dominant inheritance,Hearing Loss,2019-07-17,PS4,met,PubMed:28733840,Identified an Austrian family with AD segregating progressive late onset hearing loss who had WES identifiy the c.151C>T missense (p.Pro51Ser) variant. The family consists of 4 generations.,"Decided to use PS4 because there were  at least 12 probands with the variant and only one individual in gnomAd therefore we can use PS4

However, this is an instance where the hearing loss is progressive and late onset and therefore it is highly probable that that individual just has a mild case of HL or will develop it later on.","Decided to use PS4 because there were  at least 12 probands with the variant and only one individual in gnomAd therefore we can use PS4

However, this is an instance where the hearing loss is progressive and late onset and therefore it is highly probable that that individual just has a mild case of HL or will develop it later on. Identified an Austrian family with AD segregating progressive late onset hearing loss who had WES identifiy the c.151C>T missense (p.Pro51Ser) variant. The family consists of 4 generations.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
646,NM_000441.1(SLC26A4):c.412G>T (p.Val138Phe),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,met,PubMed:26683941,"Meta analysis of frequencies of SLLC26A4 variants among cases and controlsThis study found 185 indiviudals with the variant and found that the frequency in hearing loss was significantly higher (p<0.001) Used data from 24 articles from Asia, Europe and North America including 2294 cases and 3193 controls in multiethnic cohorts. Furthermore, there was a statistically signficant increase in frequency of the variant within just European cases-European controls. The difference in frequencies for EVA vs non-EVA populations was insignificant for this variant.",This meta analysis of SLC26A4 variants showed that p.V138F had a significantly higher frequency in hearing loss populations than in controls. They used a cohort of 2294 HL cases and 3193 multiethnic controls. They also found that this difference was sig among just European affected vs controls.,"This meta analysis of SLC26A4 variants showed that p.V138F had a significantly higher frequency in hearing loss populations than in controls. They used a cohort of 2294 HL cases and 3193 multiethnic controls. They also found that this difference was sig among just European affected vs controls. Meta analysis of frequencies of SLLC26A4 variants among cases and controlsThis study found 185 indiviudals with the variant and found that the frequency in hearing loss was significantly higher (p<0.001) Used data from 24 articles from Asia, Europe and North America including 2294 cases and 3193 controls in multiethnic cohorts. Furthermore, there was a statistically signficant increase in frequency of the variant within just European cases-European controls. The difference in frequencies for EVA vs non-EVA populations was insignificant for this variant.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
707,NM_004004.5(GJB2):c.101T>C (p.Met34Thr),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-06-28,PS4,met,PubMed:31160754,"See Table 2 from this publication
This study collected data from 15 different clinical sequencing sites and identified a total of 391 probands with the M34T allele out of 17,635 affected probands screened for GJB2. Additionally they found that 29/17,635 affected probands were homozygous for the M34T relative to 81/802,339 homozygous M34T individuals from the general population. This indicates that the homozygous genotype was significantly increased in the affected population. This was replicated in the European subpopulations, and it was also found that there were a highly significant amount of compound heterozygous individuals in the European affected subpopulation relative to that of Counsyl's carrier screening cohort. Both p values were <0.0001.",The homozygous genotype and compound het genotype with another path variant in GJB2 has been shown to be statistically enriched in patients with nonsydromic sensorineural hearing loss compared to individuals representative of the general population from carrier screening from Counsyl and/or gnomAD data.,"The homozygous genotype and compound het genotype with another path variant in GJB2 has been shown to be statistically enriched in patients with nonsydromic sensorineural hearing loss compared to individuals representative of the general population from carrier screening from Counsyl and/or gnomAD data. See Table 2 from this publication
This study collected data from 15 different clinical sequencing sites and identified a total of 391 probands with the M34T allele out of 17,635 affected probands screened for GJB2. Additionally they found that 29/17,635 affected probands were homozygous for the M34T relative to 81/802,339 homozygous M34T individuals from the general population. This indicates that the homozygous genotype was significantly increased in the affected population. This was replicated in the European subpopulations, and it was also found that there were a highly significant amount of compound heterozygous individuals in the European affected subpopulation relative to that of Counsyl's carrier screening cohort. Both p values were <0.0001.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
745,NM_004004.5(GJB2):c.109G>A (p.Val37Ile),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,met,PubMed:31160754,This is the case-control paper from the HL VCEP that demonstrates significant enrichment of V37I in patients compared to controls.,A case-control comparison was done by the HL group that demonstrated that this variant is highly enriched in cases v controls. For homozygotes the OR is 20 and the p value is <0.0001,A case-control comparison was done by the HL group that demonstrated that this variant is highly enriched in cases v controls. For homozygotes the OR is 20 and the p value is <0.0001 This is the case-control paper from the HL VCEP that demonstrates significant enrichment of V37I in patients compared to controls.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
968,NM_004004.5(GJB2):c.516G>C (p.Trp172Cys),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-10-17,PS4,met,PubMed:31195736,"220 Tuvinians (Southern Siberia, Russia) with hearing loss were tested for variants in GJB2. The p.Trp172Cys accounted for 62.9% of all mutant GJB2 alleles. It was present in 25 homozygous individuals, 7 compound heterozygous individuals (with c.-23+1G>A, and in 9 heterozygotes. This variant was not found to be biallelic in any of the 157 ethnically-matched controls, but it was observed in 6 carriers.","A 2x2 conttingency analysis of total variant alleles in cases v controls was performed. The variant is present in 66/440 case alleles and 6/314 control alleles. With a fisher exact test, the p value is <0.0001. which is highly significant.","A 2x2 conttingency analysis of total variant alleles in cases v controls was performed. The variant is present in 66/440 case alleles and 6/314 control alleles. With a fisher exact test, the p value is <0.0001. which is highly significant. 220 Tuvinians (Southern Siberia, Russia) with hearing loss were tested for variants in GJB2. The p.Trp172Cys accounted for 62.9% of all mutant GJB2 alleles. It was present in 25 homozygous individuals, 7 compound heterozygous individuals (with c.-23+1G>A, and in 9 heterozygotes. This variant was not found to be biallelic in any of the 157 ethnically-matched controls, but it was observed in 6 carriers.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
143,NM_206933.2(USH2A):c.12295-?_14133+?del,USH2A,Usher syndrome,MONDO:0019501,Likely Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-10-05,PM3,met,PubMed:26969326,"1 proband compound het with c.2276G>T, p.Cys759Phe. Unsure of phase.","3 LMM probands:
1 homozygote with Usher (0.5 points)
1 cmp het (VUS phase unknown) with hearing loss and light sensitivity (teens, 0.25 points)
1 cmp het (p.Tyr3747X, phase unknown) with hearing loss (<5 years old, 0.5 points)","3 LMM probands:
1 homozygote with Usher (0.5 points)
1 cmp het (VUS phase unknown) with hearing loss and light sensitivity (teens, 0.25 points)
1 cmp het (p.Tyr3747X, phase unknown) with hearing loss (<5 years old, 0.5 points) 1 proband compound het with c.2276G>T, p.Cys759Phe. Unsure of phase.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
742,NM_000260.4(MYO7A):c.2476G>A (p.Ala826Thr),MYO7A,Usher syndrome,MONDO:0019501,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2023-02-06,PM3,met,PubMed:22135276,"188 individuals with Usher were tested for variants in MYO7A, CDH23, PCDH15,
USH1C, USH1G, USH2A, GPR98, WHRN, CLRN1, and SLC4A7. The p.Ala826Thr variant was identified in 1 Caucasian compound heterozygous individual who also harbored the p.Trp1431X variant.","The p.Ala826Thr variant has been identified in 9 homozygous individuals and 2 compound heterozygous individuals (with two pathogenic variants). 3 points for PM3, meeting strong criteria, but was downgraded to moderate based on high FAF. ","The p.Ala826Thr variant has been identified in 9 homozygous individuals and 2 compound heterozygous individuals (with two pathogenic variants). 3 points for PM3, meeting strong criteria, but was downgraded to moderate based on high FAF.  188 individuals with Usher were tested for variants in MYO7A, CDH23, PCDH15,
USH1C, USH1G, USH2A, GPR98, WHRN, CLRN1, and SLC4A7. The p.Ala826Thr variant was identified in 1 Caucasian compound heterozygous individual who also harbored the p.Trp1431X variant.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
745,NM_004004.5(GJB2):c.109G>A (p.Val37Ile),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3,met,PubMed:31160754,>120 compound hets with the p.V37I variant,"Shen et al 2019 demonstrated in the combined analysis of at least 10 clinical sites that there were >120 compound heterozygotes with the p.Val37Ile variant. However, because the variant is also very frequent in the general population, the HL group decided to only apply this criteria at the usual strength of Moderate.","Shen et al 2019 demonstrated in the combined analysis of at least 10 clinical sites that there were >120 compound heterozygotes with the p.Val37Ile variant. However, because the variant is also very frequent in the general population, the HL group decided to only apply this criteria at the usual strength of Moderate. >120 compound hets with the p.V37I variant","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1698,NM_022124.6(CDH23):c.902G>A (p.Arg301Gln),CDH23,nonsyndromic genetic deafness,MONDO:0019497,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2020-11-02,PM3,met,PubMed:22899989,,This variant was present in 5 different individuals from 4 families all with the P240L variant in CDH23 present in trans. All individuals had sensorineural hearing loss. Because this variant was always found with the P240L variant the HL-EP decided to keep the code at the moderate level.,This variant was present in 5 different individuals from 4 families all with the P240L variant in CDH23 present in trans. All individuals had sensorineural hearing loss. Because this variant was always found with the P240L variant the HL-EP decided to keep the code at the moderate level. ,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
643,NM_206933.2(USH2A):c.5581G>A (p.Gly1861Ser),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PP1,met,PubMed:26310143,This is a case report of a Chinese family with pseudo-dominant Usher syndrome. The proband is compound het for p.Gly1861Ser and p.C934W. There is also an affected brother who has this genotype.,The proband and 1 affected sib carry this variant.,The proband and 1 affected sib carry this variant. This is a case report of a Chinese family with pseudo-dominant Usher syndrome. The proband is compound het for p.Gly1861Ser and p.C934W. There is also an affected brother who has this genotype.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
651,NM_206933.2(USH2A):c.1036A>C (p.Asn346His),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PP4,met,PubMed:22135276,Usher syndrome type II,"The patiens of compound heterozygotes or homozygotes with the mutation showed retinitis pigmentosa with hearing loss.

Enough patients were also tested for the other Usher syndrome genes and found to be negative for changes in them.  I also agree.
-MD","The patiens of compound heterozygotes or homozygotes with the mutation showed retinitis pigmentosa with hearing loss.

Enough patients were also tested for the other Usher syndrome genes and found to be negative for changes in them.  I also agree.
-MD Usher syndrome type II","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
854,NM_206933.2(USH2A):c.2276G>T (p.Cys759Phe),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-08-16,BS1,met,PubMed:25261458,Found on 0.78% (4/504) of health Spanish control chromosomes.,Found at an allele frequency of 0.33% (21/4278 with a 95% CI) in meta-cohort of healthy individuals. It has also been observed at 0.43% (95% CI of 17/2536) of across several Spanish or Latino populations published in the literature. GnomAD Latino = 0.17% (95% CI of 72/35410).,Found at an allele frequency of 0.33% (21/4278 with a 95% CI) in meta-cohort of healthy individuals. It has also been observed at 0.43% (95% CI of 17/2536) of across several Spanish or Latino populations published in the literature. GnomAD Latino = 0.17% (95% CI of 72/35410). Found on 0.78% (4/504) of health Spanish control chromosomes.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
855,NM_206933.2(USH2A):c.4714C>T (p.Leu1572Phe),USH2A,Usher syndrome,MONDO:0019501,Likely Benign,Autosomal recessive inheritance,Hearing Loss,2019-08-16,BP2,met,PubMed:26969326,"In 5 patients: in cis with c.2299delG + another het variant.
In one patient: in cis with homozygous c.2299delG",observed in cis with c.2299delG.,"observed in cis with c.2299delG. In 5 patients: in cis with c.2299delG + another het variant.
In one patient: in cis with homozygous c.2299delG","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1594,NM_000546.5(TP53):c.221C>T (p.Ala74Val),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,"Giacomelli A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.700463717

Giacomelli A549_p53WT_Nutlin-3_Z-score (DN=>0.61) = -0.214822468","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644).","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Giacomelli A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.700463717

Giacomelli A549_p53WT_Nutlin-3_Z-score (DN=>0.61) = -0.214822468",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1595,NM_000546.5(TP53):c.1163A>C (p.Glu388Ala),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2022-01-10,BS3,met,PubMed:30224644,noDNE+noLOF (p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 )),"Functional (Kato et al 2003, 100% mean transactivation activity (>75%)) 
noDNE+noLOF (Giacomelli et al. 2018, p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 ))","Functional (Kato et al 2003, 100% mean transactivation activity (>75%)) 
noDNE+noLOF (Giacomelli et al. 2018, p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 )) noDNE+noLOF (p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 ))",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1605,NM_000546.5(TP53):c.144C>A (p.Asp48Glu),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,Non-functional,"In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644). Non-functional",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2332,NM_001126112.2(TP53):c.998G>A (p.Arg333His),TP53,Li-Fraumeni syndrome 1,MONDO:0007903,Likely Benign,Autosomal dominant inheritance,TP53,2021-06-16,BS3,met,PubMed:30224644,No evidence of DNE or LOF,Kato functional; no evidence of DNE or LOF by Giacomelli; Kotler N/A; Kawaguchi shows normal tetramer formation.,Kato functional; no evidence of DNE or LOF by Giacomelli; Kotler N/A; Kawaguchi shows normal tetramer formation. No evidence of DNE or LOF,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2342,NM_000546.6(TP53):c.997C>T (p.Arg333Cys),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-02-07,BS3,met,PubMed:39060302,"showed comparable or higher expression levels of CDKN1A, MDM2, GADD45A and PMAIP1 compared to WT condition","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 30224644).","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 30224644). showed comparable or higher expression levels of CDKN1A, MDM2, GADD45A and PMAIP1 compared to WT condition",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2659,NM_000546.5(TP53):c.11C>T (p.Pro4Leu),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,"No dominant negative effect (p53WTNutlin3 Z-score -0.367(< 0.61)), and no loss of function (Etoposide Z-score 0.356(> -0.21 )). ","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).
","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).
 No dominant negative effect (p53WTNutlin3 Z-score -0.367(< 0.61)), and no loss of function (Etoposide Z-score 0.356(> -0.21 )). ",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2662,NM_000546.5(TP53):c.1151T>C (p.Met384Thr),TP53,Li-Fraumeni syndrome,MONDO:0018875,Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,noDNE+noLOF,"In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).
","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).
 noDNE+noLOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2663,NM_000546.5(TP53):c.875A>G (p.Lys292Arg),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,noDNE+noLOF,"In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644).","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). noDNE+noLOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2664,NM_000546.6(TP53):c.556G>A (p.Asp186Asn),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,"A549_p53WT_Nutlin-3_Z-score (DN=>0.61)
 = 0.095621624; A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.307883038","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644).","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). A549_p53WT_Nutlin-3_Z-score (DN=>0.61)
 = 0.095621624; A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.307883038",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2665,NM_000546.5(TP53):c.37C>T (p.Pro13Ser),TP53,Li-Fraumeni syndrome 1,MONDO:0007903,Uncertain Significance,Autosomal dominant inheritance,TP53,2022-06-27,BS3,met,PubMed:30224644,A549_p53WT_Nutlin-3_Z-score (DN=>0.61) = -0.45635397; A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.124669083,"Transactivation assays in yeast demonstrate a functional allele (99.75% activity, based on data from Kato et al) and there is no evidence of a dominant negative effect (DNE) and no evidence of LOF from Giacomelli et al","Transactivation assays in yeast demonstrate a functional allele (99.75% activity, based on data from Kato et al) and there is no evidence of a dominant negative effect (DNE) and no evidence of LOF from Giacomelli et al A549_p53WT_Nutlin-3_Z-score (DN=>0.61) = -0.45635397; A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.124669083",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2667,NM_000546.5(TP53):c.353C>T (p.Thr118Ile),TP53,Li-Fraumeni syndrome 1,MONDO:0007903,Uncertain Significance,Autosomal dominant inheritance,TP53,2021-09-24,BS3,met,PubMed:30224644,noLOF/noDNE,"Kato functional, Giacomelli noLOF/noDNE, Kotler noLOF","Kato functional, Giacomelli noLOF/noDNE, Kotler noLOF noLOF/noDNE",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2668,NM_000546.6(TP53):c.188C>G (p.Ala63Gly),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:35043155,Predicted functional by TP53_PROF,"In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).
","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).
 Predicted functional by TP53_PROF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2719,NM_001126112.2(TP53):c.188C>T (p.Ala63Val),TP53,Li-Fraumeni syndrome,MONDO:0018875,Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,No LOF,"In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644). No LOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
9457,NM_000546.6(TP53):c.143A>G (p.Asp48Gly),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,noLOF,"In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644). noLOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1597,NM_000546.5(TP53):c.396G>C (p.Lys132Asn),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Pathogenic,Autosomal dominant inheritance,TP53,2022-03-18,PS3,met,PubMed:30224644,Shows DNE and LOF,"Experimental studies show this variant to be non-functional (Kato 2003) and to demonstrate both dominant negative effect (DNE) and loss of function (LOF) (Dearth 2007, Giacomelli 2018 and Kotler 2018).","Experimental studies show this variant to be non-functional (Kato 2003) and to demonstrate both dominant negative effect (DNE) and loss of function (LOF) (Dearth 2007, Giacomelli 2018 and Kotler 2018). Shows DNE and LOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2747,NM_005027.4(PIK3R2):c.1117G>A (p.Gly373Arg),PIK3R2,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-17,PS4,met,PubMed:28086757,"2 w/ OFC >2 SD, ventriculomegaly and PMG","16 COSMIC, 27 cBioPortal
This variant met criteria to meet PS4_VS >16 ","16 COSMIC, 27 cBioPortal
This variant met criteria to meet PS4_VS >16  2 w/ OFC >2 SD, ventriculomegaly and PMG",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2747,NM_005027.4(PIK3R2):c.1117G>A (p.Gly373Arg),PIK3R2,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-17,PS4,met,PubMed:22729224,"13 w/ MPPH: hydrocephalus, ventriculomegaly and PMG","16 COSMIC, 27 cBioPortal
This variant met criteria to meet PS4_VS >16 ","16 COSMIC, 27 cBioPortal
This variant met criteria to meet PS4_VS >16  13 w/ MPPH: hydrocephalus, ventriculomegaly and PMG",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2752,NM_004958.4(MTOR):c.4448G>A (p.Cys1483Tyr),MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-17,PS4,met,PubMed:26619011,1 tumor sample,2 COSMIC tumor samples,2 COSMIC tumor samples 1 tumor sample,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2755,NM_004958.3(MTOR):c.4447T>C (p.Cys1483Arg),MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PS4,met,PubMed:28864461,FCD Iib w/ neuopath,3 tumor samples in COSMIC,3 tumor samples in COSMIC FCD Iib w/ neuopath,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2759,NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS4,met,PubMed:22729224,"LR09-006 MCAP, LR11-070 had megalencephaly,vascular malformation,connective tissue dysplasia, ventriculomegaly and cerebellar tonsillar ectopia, LR06-341 had overgrowth, vasulcar malformation, connective tissued dyspalsia, and polymicrogyria",also present in 2 tumor samples in COSMIC Upgraded to very strong,"also present in 2 tumor samples in COSMIC Upgraded to very strong LR09-006 MCAP, LR11-070 had megalencephaly,vascular malformation,connective tissue dysplasia, ventriculomegaly and cerebellar tonsillar ectopia, LR06-341 had overgrowth, vasulcar malformation, connective tissued dyspalsia, and polymicrogyria",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2761,NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS4,met,PubMed:22729224,"001P, 333, 261 all have MCAP","15MCAP, 104 tumors in cosmic","15MCAP, 104 tumors in cosmic 001P, 333, 261 all have MCAP",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2761,NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS4,met,PubMed:27631024,10 individuals with MCAP,"15MCAP, 104 tumors in cosmic","15MCAP, 104 tumors in cosmic 10 individuals with MCAP",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2773,NM_004958.3:c.4468T>C,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Likely Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PS4,met,PubMed:27830187,macrocephaly and mild ID,, macrocephaly and mild ID,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2775,NM_004958.3(MTOR):c.6644C>T (p.Ser2215Phe),MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS4,met,PubMed:27830187,"2 IIb, 1 IIa with somatic mutations (no functional assay)",19 tumor samples in COSMIC,"19 tumor samples in COSMIC 2 IIb, 1 IIa with somatic mutations (no functional assay)",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2778,NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PS4,met,PubMed:29988677,"57‐year‐old man who came to our attention for an asymmetric segmental overgrowth of the left foot and ankle, characterized by the presence of bone and connective tissue hyperplastic lesions, the patient showed macrosomia of the left foot and ankle, varus leg deformity and lumps around the knee, and hyperplasia on the left sole",over 15 tumor samples in COSMIC,"over 15 tumor samples in COSMIC 57‐year‐old man who came to our attention for an asymmetric segmental overgrowth of the left foot and ankle, characterized by the presence of bone and connective tissue hyperplastic lesions, the patient showed macrosomia of the left foot and ankle, varus leg deformity and lumps around the knee, and hyperplasia on the left sole",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2761,NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS2,met,PubMed:22729224,"LR08-261 (12% blood 41% buccal), LR06-333 (14% LCL and 15% saliva)",," LR08-261 (12% blood 41% buccal), LR06-333 (14% LCL and 15% saliva)",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2775,NM_004958.3(MTOR):c.6644C>T (p.Ser2215Phe),MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS2,met,PubMed:27830187,"2 IIb, 1 IIa with somatic mutations (no functional assay)",," 2 IIb, 1 IIa with somatic mutations (no functional assay)",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2767,NM_001386501.1:c.3127G>T,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Uncertain Significance,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,BP2,met,PubMed:27830187,This variant was identified in CIS with a known pathogenic variant c.4379T>C,, This variant was identified in CIS with a known pathogenic variant c.4379T>C,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
5619,NM_007294.4(BRCA1):c.191G>A (p.Cys64Tyr),BRCA1,BRCA1-related cancer predisposition,MONDO:0011450,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-11,PS3,met,PubMed:30209399,Deleterious,Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). ,Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met).  Deleterious,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_version=1.2.0.csv
5629,NM_007294.4(BRCA1):c.5089T>C (p.Cys1697Arg),BRCA1,BRCA1-related cancer predisposition,MONDO:0011450,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,PS3,met,PubMed:30209399,Scores non-functional,"Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met).","Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met). Scores non-functional",ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_version=1.2.0.csv
5643,NM_000059.4(BRCA2):c.8168A>C (p.Asp2723Ala),BRCA2,BRCA2-related cancer predisposition,MONDO:0012933,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,PS3,met,PubMed:33293522,Complete functional impact in assay measuring viability of knockout mouse embryonic stem cells,"Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met). ","Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met).  Complete functional impact in assay measuring viability of knockout mouse embryonic stem cells",ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
5643,NM_000059.4(BRCA2):c.8168A>C (p.Asp2723Ala),BRCA2,BRCA2-related cancer predisposition,MONDO:0012933,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,PS3,met,PubMed:33609447,Complete functional impact in homology directed repair assay,"Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met). ","Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met).  Complete functional impact in homology directed repair assay",ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
5645,NM_000059.4(BRCA2):c.9227G>T (p.Gly3076Val),BRCA2,BRCA2-related cancer predisposition,MONDO:0012933,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,PS3,met,PubMed:33609447,Non functional,Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 33609447) (PS3 met). ,Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 33609447) (PS3 met).  Non functional,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
5611,NM_000059.4(BRCA2):c.831T>G (p.Asn277Lys),BRCA2,BRCA2-related cancer predisposition,MONDO:0012933,Benign,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,BS3,met,PubMed:33293522,Variant labelled as functional,Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 33293522) (BS3 met). ,Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 33293522) (BS3 met).  Variant labelled as functional,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
797,NM_001754.4(RUNX1):c.602G>A (p.Arg201Gln),RUNX1,hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2019-08-02,PP1,met,PubMed:28748566,"2 segregations - 3 individuals with chronic thrombocytopenia, no MDS",4 segregations counted additively across publications,"4 segregations counted additively across publications 2 segregations - 3 individuals with chronic thrombocytopenia, no MDS",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
797,NM_001754.4(RUNX1):c.602G>A (p.Arg201Gln),RUNX1,hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2019-08-02,PS4,met,PubMed:28748566,1 proband (Patient 64) with lifelong history of severe thrombocytopenia and bleeding tendency. She developed myelodysplasia when aged 65 years and 1 proband with chronic thrombocytopenia.,4 probands counted across publications.,4 probands counted across publications. 1 proband (Patient 64) with lifelong history of severe thrombocytopenia and bleeding tendency. She developed myelodysplasia when aged 65 years and 1 proband with chronic thrombocytopenia.,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1771,NM_001754.5(RUNX1):c.484A>G (p.Arg162Gly),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-03-26,PM1,met,PubMed:28231333,"“In Runx1, Arg135 and Arg139 interact with G105–A107 and G4–C6, respectively (green), while Arg80 interacts with A106–T107, and Lys83 interacts with T107, T109, and A7 (yellow).”","This variant affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1).","This variant affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). “In Runx1, Arg135 and Arg139 interact with G105–A107 and G4–C6, respectively (green), while Arg80 interacts with A106–T107, and Lys83 interacts with T107, T109, and A7 (yellow).”",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
5879,NM_001754.5(RUNX1):c.330G>C (p.Lys110Asn),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Likely Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2023-12-09,PS3,met,PubMed:22649608,"K83N was transduced into SC1 murine fibroblasts, and reduction of this variant's mRNA was seen upon transfection with short interfering-RNA (posttranscriptional silencing of target gene). K83N was transduced into HEK293T cells, and reduction of this variant's mRNA was seen upon transfection with short hairpin-RNA (longer-lasting gene silencing). These results were confirmed by RT-PCR and flow cytometry.","The variant in a transactivation assay using the M-CSF promoter exhibited a 70% reduction; the mutant protein was also unable to bind DNA whether or or not in the presence of the CBFβ subunit, without affecting CBFβ heterodimerization and nuclear localization (PMID: 10068652; PMID: 11830488). Additional studies of the mutant protein showed that it decreases the ratio of erythroid to myeloid colonies, results in immortalization of cells, and the accumulation of myeloblasts and dysplastic progenitors (PMID: 17234761).","The variant in a transactivation assay using the M-CSF promoter exhibited a 70% reduction; the mutant protein was also unable to bind DNA whether or or not in the presence of the CBFβ subunit, without affecting CBFβ heterodimerization and nuclear localization (PMID: 10068652; PMID: 11830488). Additional studies of the mutant protein showed that it decreases the ratio of erythroid to myeloid colonies, results in immortalization of cells, and the accumulation of myeloblasts and dysplastic progenitors (PMID: 17234761). K83N was transduced into SC1 murine fibroblasts, and reduction of this variant's mRNA was seen upon transfection with short interfering-RNA (posttranscriptional silencing of target gene). K83N was transduced into HEK293T cells, and reduction of this variant's mRNA was seen upon transfection with short hairpin-RNA (longer-lasting gene silencing). These results were confirmed by RT-PCR and flow cytometry.",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
510,NM_004360.4(CDH1):c.1137G>A (p.Thr379=),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4,met,PubMed:27995193,c.1137G>A variant identified in a patient with SRC cancer meeting IGCLC criteria for HDGC.,Proband is an obligate carrier with a strong family history of DGC.  Seven HDGC families with the c.1137G>A variant have been reported in the literature. Total of 8 families.,Proband is an obligate carrier with a strong family history of DGC.  Seven HDGC families with the c.1137G>A variant have been reported in the literature. Total of 8 families. c.1137G>A variant identified in a patient with SRC cancer meeting IGCLC criteria for HDGC.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
522,NM_004360.4(CDH1):c.1679C>G (p.Thr560Arg),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4,met,PubMed:27880784,Shows multiple family members with the CDH1 mutation and all 3 have gastric cancer,Four published families plus internal lab data (SCV000580704.2),Four published families plus internal lab data (SCV000580704.2) Shows multiple family members with the CDH1 mutation and all 3 have gastric cancer,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1100,NM_004360.4(CDH1):c.1565+2dupT,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-30,PS4,met,PubMed:25315765,One family from the US that meets HDGC clinical criteria,"Six families that meet HDGC clinical criteria (PMID: 18391748, 23709761, 25315765, 26072394, SCV000665426.2). Three families that do not meet HDGC clinical criteria due to lack of information (SCV000665426.2)","Six families that meet HDGC clinical criteria (PMID: 18391748, 23709761, 25315765, 26072394, SCV000665426.2). Three families that do not meet HDGC clinical criteria due to lack of information (SCV000665426.2) One family from the US that meets HDGC clinical criteria",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1637,NM_004360.5(CDH1):c.387+5G>A,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Benign,Autosomal dominant inheritance,CDH1,2023-08-10,BS3,met,PubMed:31642931,RNA studies demonstrate no abnormal splicing,RNA studies demonstrate no abnormal splicing (SCV000186607.5).,RNA studies demonstrate no abnormal splicing (SCV000186607.5). RNA studies demonstrate no abnormal splicing,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1799,NM_000419.4(ITGA2B):c.2965G>A (p.Ala989Thr),ITGA2B,Glanzmann's thrombasthenia,MONDO:0010119,Likely Benign,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,BP2,met,PubMed:25539746,"GT-6 was described to have triple heterozygosity with a paternally inherited nonsense, Glu538Ter, variant and both Val982Met and Ala958Thr occurring as de novo variants. No confirmation was reported that the variants are in trans phase.","This variant has been observed in cis with the VCEP-curated pathogenic variant Val982Met (PMID 15099289 and 20020534). In an additional proband (PMID 25539746), this variant has also been reported in combination with Val982Met and Glu538Ter, however, the phase of the variants was not confirmed.","This variant has been observed in cis with the VCEP-curated pathogenic variant Val982Met (PMID 15099289 and 20020534). In an additional proband (PMID 25539746), this variant has also been reported in combination with Val982Met and Glu538Ter, however, the phase of the variants was not confirmed. GT-6 was described to have triple heterozygosity with a paternally inherited nonsense, Glu538Ter, variant and both Val982Met and Ala958Thr occurring as de novo variants. No confirmation was reported that the variants are in trans phase.",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
1851,NM_000419.4(ITGA2B):c.2944G>A (p.Val982Met),ITGA2B,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PM3,met,PubMed:25539746,"GT-6 was described to have triple heterozygosity with a paternally inherited nonsense, Glu538Ter, pathogenic variant and both Val982Met and Ala958Thr occurring as de novo variants. However it was asserted that Ala989Thr was a polymorphism and Val982Met is the second variant of interest in this patient. No confirmation was reported that the variants are in trans phase. 0.5pt","This variant has been observed in compound heterozygotes; once with the splice variant c.1946+1G>A (classified as Pathogenic by the ClinGen Platelet Disorders VCEP), as well as with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP).","This variant has been observed in compound heterozygotes; once with the splice variant c.1946+1G>A (classified as Pathogenic by the ClinGen Platelet Disorders VCEP), as well as with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP). GT-6 was described to have triple heterozygosity with a paternally inherited nonsense, Glu538Ter, pathogenic variant and both Val982Met and Ala958Thr occurring as de novo variants. However it was asserted that Ala989Thr was a polymorphism and Val982Met is the second variant of interest in this patient. No confirmation was reported that the variants are in trans phase. 0.5pt",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
1851,NM_000419.4(ITGA2B):c.2944G>A (p.Val982Met),ITGA2B,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PM3,met,PubMed:28983057,"Case 37 is a compound heterozygote for this Val982Met variant and a c.2965del frameshift variant. No confirmation was reported that the variants are in trans phase. However, to avoid circularity the proband was counted only towards the classification of c.2965del not Val982Met.","This variant has been observed in compound heterozygotes; once with the splice variant c.1946+1G>A (classified as Pathogenic by the ClinGen Platelet Disorders VCEP), as well as with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP).","This variant has been observed in compound heterozygotes; once with the splice variant c.1946+1G>A (classified as Pathogenic by the ClinGen Platelet Disorders VCEP), as well as with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP). Case 37 is a compound heterozygote for this Val982Met variant and a c.2965del frameshift variant. No confirmation was reported that the variants are in trans phase. However, to avoid circularity the proband was counted only towards the classification of c.2965del not Val982Met.",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
1851,NM_000419.4(ITGA2B):c.2944G>A (p.Val982Met),ITGA2B,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PS2,met,PubMed:25539746,"This Val982Met variant was found to occur de novo in patient GT-6. It was not present in the father, mother, or brother of the patient. Paternity and maternity were confirmed. The individual is compound heterozygous with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP). 2pt","This variant was found to occur de novo in one proband (PMID: 25539746). The individual is compound heterozygous with a pathogenic nonsense, Glu538Ter, variant provisionally classified as Pathogenic by the ClinGen Platelet Disorders VCEP.","This variant was found to occur de novo in one proband (PMID: 25539746). The individual is compound heterozygous with a pathogenic nonsense, Glu538Ter, variant provisionally classified as Pathogenic by the ClinGen Platelet Disorders VCEP. This Val982Met variant was found to occur de novo in patient GT-6. It was not present in the father, mother, or brother of the patient. Paternity and maternity were confirmed. The individual is compound heterozygous with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP). 2pt",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
2085,NM_004360.5(CDH1):c.1057G>A (p.Glu353Lys),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-24,PS3,met,PubMed:32133419,"RNA studies demonstrate abnormal splicing, r.1055_1137del (out-of-frame). ",PMID: 32133419 - RNA studies demonstrate abnormal splicing in the set of samples tested (Ambry internal data) - CDH1 r.1055_1137del (out-of-frame).,"PMID: 32133419 - RNA studies demonstrate abnormal splicing in the set of samples tested (Ambry internal data) - CDH1 r.1055_1137del (out-of-frame). RNA studies demonstrate abnormal splicing, r.1055_1137del (out-of-frame). ",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
2168,NM_003159.2(CDKL5):c.533G>A (p.Arg178Gln),CDKL5,CDKL5 disorder,MONDO:0100039,Pathogenic,X-linked inheritance (dominant (HP:0001423)),Rett and Angelman-like Disorders,2021-05-10,PS4,met,PubMed:24564546,The p.Arg178Gln variant was observed in a male individual with CDKL5 disease.,"The p.Arg178Gln variant has been observed in at least 7 other individuals with CDKL5 disease (PMIDs 26482601, 21770923,  29852413, 29190809, 24564546, ClinVar Variation ID 94113).","The p.Arg178Gln variant has been observed in at least 7 other individuals with CDKL5 disease (PMIDs 26482601, 21770923,  29852413, 29190809, 24564546, ClinVar Variation ID 94113). The p.Arg178Gln variant was observed in a male individual with CDKL5 disease.",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
2168,NM_003159.2(CDKL5):c.533G>A (p.Arg178Gln),CDKL5,CDKL5 disorder,MONDO:0100039,Pathogenic,X-linked inheritance (dominant (HP:0001423)),Rett and Angelman-like Disorders,2021-05-10,PS4,met,PubMed:29190809,The p.Arg178Gln variant was observed in a female individual with epileptic encephalopathy.,"The p.Arg178Gln variant has been observed in at least 7 other individuals with CDKL5 disease (PMIDs 26482601, 21770923,  29852413, 29190809, 24564546, ClinVar Variation ID 94113).","The p.Arg178Gln variant has been observed in at least 7 other individuals with CDKL5 disease (PMIDs 26482601, 21770923,  29852413, 29190809, 24564546, ClinVar Variation ID 94113). The p.Arg178Gln variant was observed in a female individual with epileptic encephalopathy.",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
2227,NM_001083962.1(TCF4):c.759C>G (p.Ser253Arg),TCF4,Pitt-Hopkins syndrome,MONDO:0012589,Likely Pathogenic,Autosomal dominant inheritance,Rett and Angelman-like Disorders,2021-05-17,PP4,met,PubMed:26993267,The p.Ser253Arg variant in TCF4 has been reported in 2 unconfirmed de novo occurrences in an individual with Pitt–Hopkins syndrome and in an individual with early infantile epileptic encephalopathy.,"The p.Ser253Arg variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt–Hopkins syndrome (PMID 26993267, described as p.Ser355Arg)","The p.Ser253Arg variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt–Hopkins syndrome (PMID 26993267, described as p.Ser355Arg) The p.Ser253Arg variant in TCF4 has been reported in 2 unconfirmed de novo occurrences in an individual with Pitt–Hopkins syndrome and in an individual with early infantile epileptic encephalopathy.",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version4.0.0_version=4.0.0.csv
2358,NM_000527.5(LDLR):c.2575G>A (p.Val859Met),LDLR,"hypercholesterolemia, familial",MONDO:0007750,Likely Benign,Semidominant inheritance,Familial Hypercholesterolemia,2021-06-24,BS3,met,PubMed:25386756,"Expression >90%, uptake 90%, degradation of 125I-LDL 90%","PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%.","PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%. Expression >90%, uptake 90%, degradation of 125I-LDL 90%",ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
2488,NM_000212.2:c.31T>C,ITGB3,Glanzmann thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2023-12-13,PM3,met,PubMed:28748566,Patient 1 is homozygous for the Trp11Arg variant.,"This Trp11Arg variant has been observed twice in homozygous cases in the literature (PMIDs: 25728920, 28748566). 1pt  And confirmed in trans with Likely Pathogenic variant Cys486Trp (PMID: 25373348), not considered here to avoid circularity.","This Trp11Arg variant has been observed twice in homozygous cases in the literature (PMIDs: 25728920, 28748566). 1pt  And confirmed in trans with Likely Pathogenic variant Cys486Trp (PMID: 25373348), not considered here to avoid circularity. Patient 1 is homozygous for the Trp11Arg variant.",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
3115,NC_012920.1:m.9055G>A,MT-ATP6,mitochondrial disease,MONDO:0044970,Benign,Mitochondrial inheritance,Mitochondrial Diseases,2022-01-05,BA1,met,PubMed:24104924,Establishes haplogroup K as common in Ashkenazi Jews,"The highest population minor allele frequency in GenBank (51,863 GenBank sequences) is 4.24%; in gnomad v3.1.2 is 5.393% (homoplasmic occurrences); and in Helix (196,554 sequences, 91% lineage N bias) is 8.05%. These are all higher than the ClinGen Mitochondrial  Disease Nuclear and Mitochondrial Variant Curation Expert Panel - mtDNA specifications - threshold (>0.01 or 1%). Furthermore, m.9055G>A is a haplogroup-defining variant for K at 99.7%. It is also found in Z3b (100%), U8b (100%).  Therefore, this meets this criterion (BA1).

As a note, the K haplogroup is common in the Ashkenazi Jewish population. m.9055 G>A is a haplogroup-defining variant for K at 99.7%. Subgroup frequencies are K1 (99.3%), K2 (99.7%). However, if an individual with this variant is a member of a different haplogroup than those where the variant is a marker, consider further evaluation.
","The highest population minor allele frequency in GenBank (51,863 GenBank sequences) is 4.24%; in gnomad v3.1.2 is 5.393% (homoplasmic occurrences); and in Helix (196,554 sequences, 91% lineage N bias) is 8.05%. These are all higher than the ClinGen Mitochondrial  Disease Nuclear and Mitochondrial Variant Curation Expert Panel - mtDNA specifications - threshold (>0.01 or 1%). Furthermore, m.9055G>A is a haplogroup-defining variant for K at 99.7%. It is also found in Z3b (100%), U8b (100%).  Therefore, this meets this criterion (BA1).

As a note, the K haplogroup is common in the Ashkenazi Jewish population. m.9055 G>A is a haplogroup-defining variant for K at 99.7%. Subgroup frequencies are K1 (99.3%), K2 (99.7%). However, if an individual with this variant is a member of a different haplogroup than those where the variant is a marker, consider further evaluation.
 Establishes haplogroup K as common in Ashkenazi Jews",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
3115,NC_012920.1:m.9055G>A,MT-ATP6,mitochondrial disease,MONDO:0044970,Benign,Mitochondrial inheritance,Mitochondrial Diseases,2022-01-05,BA1,met,PubMed:32461654,gnomAD v3.1 has a homoplasmic AF of 5.393% in 56368 mt sequences,"The highest population minor allele frequency in GenBank (51,863 GenBank sequences) is 4.24%; in gnomad v3.1.2 is 5.393% (homoplasmic occurrences); and in Helix (196,554 sequences, 91% lineage N bias) is 8.05%. These are all higher than the ClinGen Mitochondrial  Disease Nuclear and Mitochondrial Variant Curation Expert Panel - mtDNA specifications - threshold (>0.01 or 1%). Furthermore, m.9055G>A is a haplogroup-defining variant for K at 99.7%. It is also found in Z3b (100%), U8b (100%).  Therefore, this meets this criterion (BA1).

As a note, the K haplogroup is common in the Ashkenazi Jewish population. m.9055 G>A is a haplogroup-defining variant for K at 99.7%. Subgroup frequencies are K1 (99.3%), K2 (99.7%). However, if an individual with this variant is a member of a different haplogroup than those where the variant is a marker, consider further evaluation.
","The highest population minor allele frequency in GenBank (51,863 GenBank sequences) is 4.24%; in gnomad v3.1.2 is 5.393% (homoplasmic occurrences); and in Helix (196,554 sequences, 91% lineage N bias) is 8.05%. These are all higher than the ClinGen Mitochondrial  Disease Nuclear and Mitochondrial Variant Curation Expert Panel - mtDNA specifications - threshold (>0.01 or 1%). Furthermore, m.9055G>A is a haplogroup-defining variant for K at 99.7%. It is also found in Z3b (100%), U8b (100%).  Therefore, this meets this criterion (BA1).

As a note, the K haplogroup is common in the Ashkenazi Jewish population. m.9055 G>A is a haplogroup-defining variant for K at 99.7%. Subgroup frequencies are K1 (99.3%), K2 (99.7%). However, if an individual with this variant is a member of a different haplogroup than those where the variant is a marker, consider further evaluation.
 gnomAD v3.1 has a homoplasmic AF of 5.393% in 56368 mt sequences",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
4017,NM_001306179.2:c.613A>C,HNF1A,monogenic diabetes,MONDO:0015967,Uncertain Significance,Autosomal dominant inheritance,Monogenic Diabetes,2022-08-04,PM1,met,PubMed:28410371,Lys205 is an amino acid that directly binds DNA.,"This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).","This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Lys205 is an amino acid that directly binds DNA.",ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv
5162,NM_000261.2:c.1348A>T,MYOC,juvenile open angle glaucoma,MONDO:0020367,Likely Pathogenic,Autosomal dominant inheritance,Glaucoma,2023-06-01,PS3,met,PubMed:35615698,"A transgenic mouse model carrying human MYOC N450Y and displaying non secretion of N450Y protein in vivo exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) ","A transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825).","A transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825). A transgenic mouse model carrying human MYOC N450Y and displaying non secretion of N450Y protein in vivo exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) ",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
5162,NM_000261.2:c.1348A>T,MYOC,juvenile open angle glaucoma,MONDO:0020367,Likely Pathogenic,Autosomal dominant inheritance,Glaucoma,2023-06-01,PS3,met,PubMed:32818018,"The N450Y protein is not secreted.
This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). ","A transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825).","A transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825). The N450Y protein is not secreted.
This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). ",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
6945,NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr),SCN2A,complex neurodevelopmental disorder,MONDO:0100038,Pathogenic,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-07,PS3,met,PubMed:32400968,Whole-cell patch-clamp e-physiology recordings of voltage-gated Na+ currents in HEK293T cell expressing the A1773T and WT Na+ channels showed that the A1773T channel exhibited a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density with a half-maximal activation potential at ~10 mV the of −68.76 ± 2.01 mV for the A1773T compared to (−58.57 ± 1.40 mV) in the WT (Figure 2d). The mutant showed a longer recovery time constant τ1 from fast-inactivation compared to WT. ,"Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed  a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968)(PS3_Strong)","Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed  a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968)(PS3_Strong) Whole-cell patch-clamp e-physiology recordings of voltage-gated Na+ currents in HEK293T cell expressing the A1773T and WT Na+ channels showed that the A1773T channel exhibited a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density with a half-maximal activation potential at ~10 mV the of −68.76 ± 2.01 mV for the A1773T compared to (−58.57 ± 1.40 mV) in the WT (Figure 2d). The mutant showed a longer recovery time constant τ1 from fast-inactivation compared to WT. ",ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion2.0.0_version=2.0.0.csv
6969,NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln),SCN8A,complex neurodevelopmental disorder,MONDO:0100038,Pathogenic,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-09,PS3,met,PubMed:26900580,The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation.,The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation.,The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation. The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation.,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion2.0.0_version=2.0.0.csv
6977,NM_006922.4(SCN3A):c.5407G>A (p.Asp1803Asn),SCN3A,developmental and epileptic encephalopathy,MONDO:0100062,Benign,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-09,PM1,met,PubMed:31871067,"Variant is located within a Pathogenic Enriched Regions (PERs) 
PER: Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants",This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP.,"This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP. Variant is located within a Pathogenic Enriched Regions (PERs) 
PER: Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants",ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion2.0.0_version=2.0.0.csv
6977,NM_006922.4(SCN3A):c.5407G>A (p.Asp1803Asn),SCN3A,developmental and epileptic encephalopathy,MONDO:0100062,Benign,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-09,PM1,met,PubMed:32183904,"	
Variant is located within a Pathogenic Enriched Regions (PERs) 
PER: Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants",This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP.,"This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP. 	
Variant is located within a Pathogenic Enriched Regions (PERs) 
PER: Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants",ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion2.0.0_version=2.0.0.csv
6983,NM_021007.3:c.2558G>A,SCN2A,complex neurodevelopmental disorder,MONDO:0100038,Pathogenic,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-09,PS3,met,PubMed:31558572,Peak current 51% of WT,"Heterologous expression with voltage clamping showed decreased peak current, 51% of wildtype. This exceeds the threshold of <72.7% for PS3. ","Heterologous expression with voltage clamping showed decreased peak current, 51% of wildtype. This exceeds the threshold of <72.7% for PS3.  Peak current 51% of WT",ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion2.0.0_version=2.0.0.csv
7204,NM_000551.4(VHL):c.264G>T (p.Trp88Cys),VHL,von Hippel-Lindau disease,MONDO:0008667,Likely Pathogenic,Autosomal dominant inheritance,VHL,2024-06-25,PM1,met,PubMed:35475554,"Figure 4, hotspot analysis shows Trp88Cys is a germline hotspot in VHL. ","This variant is located in a mutational hotspot (PMID:35475554). There are multiple other nucleotide and amino acid substitutions at this position in ClinVar, including:  NM_000551.4(VHL):c.264G>C (p.Trp88Cys), NM_000551.4(VHL):c.263G>C (p.Trp88Ser), NM_000551.4(VHL):c.262T>A (p.Trp88Arg), NM_000551.4(VHL):c.262T>C (p.Trp88Arg). (PM1)","This variant is located in a mutational hotspot (PMID:35475554). There are multiple other nucleotide and amino acid substitutions at this position in ClinVar, including:  NM_000551.4(VHL):c.264G>C (p.Trp88Cys), NM_000551.4(VHL):c.263G>C (p.Trp88Ser), NM_000551.4(VHL):c.262T>A (p.Trp88Arg), NM_000551.4(VHL):c.262T>C (p.Trp88Arg). (PM1) Figure 4, hotspot analysis shows Trp88Cys is a germline hotspot in VHL. ",ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
7553,NM_001369369.1(FOXN1):c.1370del (p.His457fs),FOXN1,"T-cell immunodeficiency, congenital alopecia, and nail dystrophy",MONDO:0011132,Pathogenic,Semidominant inheritance,Severe Combined Immunodeficiency Disease,2024-07-29,PS3,met,PubMed:34860543,"The transcriptional activity of wild-type and Δ550 FOXN1 were assayed in TEC4D6 cells cotransfected with a reporter plasmid containing a luciferase gene under the transcriptional control of the FOXN1-specific Psmb11 promoter, which normally controls β5t expression in TEC (2). Wild-type FOXN1 activated the luciferase gene in a gene dosage sensitive manner (Fig. 1E), whereas Δ550 FOXN1 failed to activate luciferase gene expression (Fig. 1F).","The heterozygous expression of Δ505 Foxn1 in mice, the ortholog of the human mutation, results in thymic hypoplasia, a limited population of peripheral T cells, and changes in the composition of the TEC scaffold.  FOXN1WT/Δ505 mice displayed a normal coat, whereas mice homozygous for the Δ505 mutation (designated FOXN1Δ505/Δ505) were hairless and lacked a thymus and peripheral T cells (fig. S2I). 

","The heterozygous expression of Δ505 Foxn1 in mice, the ortholog of the human mutation, results in thymic hypoplasia, a limited population of peripheral T cells, and changes in the composition of the TEC scaffold.  FOXN1WT/Δ505 mice displayed a normal coat, whereas mice homozygous for the Δ505 mutation (designated FOXN1Δ505/Δ505) were hairless and lacked a thymus and peripheral T cells (fig. S2I). 

 The transcriptional activity of wild-type and Δ550 FOXN1 were assayed in TEC4D6 cells cotransfected with a reporter plasmid containing a luciferase gene under the transcriptional control of the FOXN1-specific Psmb11 promoter, which normally controls β5t expression in TEC (2). Wild-type FOXN1 activated the luciferase gene in a gene dosage sensitive manner (Fig. 1E), whereas Δ550 FOXN1 failed to activate luciferase gene expression (Fig. 1F).",ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXN1Version1.0.0_version=1.0.0.csv
7659,NM_000552.5(VWF):c.3946G>A (p.Val1316Met),VWF,von Willebrand disease type 2B,MONDO:0015629,Pathogenic,Autosomal dominant inheritance,von Willebrand Disease,2024-08-19,PS3,met,PubMed:27212476,"A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3).","A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3).","A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3). A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3).",ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
7726,NM_000552.5(VWF):c.8317T>C (p.Cys2773Arg),VWF,von Willebrand disease type 2A,MONDO:0015628,Pathogenic,Autosomal dominant inheritance,von Willebrand Disease,2024-08-13,PS3,met,PubMed:34136746,"Fibronectin binding to recombinant VWF found p.2773R did not bind.

This is not an assay considered by the VWD VCEP for PS3.","Multimerization assay performed with the Cys2773Arg recombinant mutant and wt vWF expressed by COS7 cells showed abnormal multimers, including loss of HMWM and an extra central band, indicating that this variant has a damaging effect on protein function. Additionally, collagen binding was disrupted. (PMID: 11264172 Fig. 5; PS3) Similar results were also reported in PMID:24598842.
","Multimerization assay performed with the Cys2773Arg recombinant mutant and wt vWF expressed by COS7 cells showed abnormal multimers, including loss of HMWM and an extra central band, indicating that this variant has a damaging effect on protein function. Additionally, collagen binding was disrupted. (PMID: 11264172 Fig. 5; PS3) Similar results were also reported in PMID:24598842.
 Fibronectin binding to recombinant VWF found p.2773R did not bind.

This is not an assay considered by the VWD VCEP for PS3.",ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
7726,NM_000552.5(VWF):c.8317T>C (p.Cys2773Arg),VWF,von Willebrand disease type 2A,MONDO:0015628,Pathogenic,Autosomal dominant inheritance,von Willebrand Disease,2024-08-13,PS3,met,PubMed:30645640,Found similar defects in dimerization using atomic force microscopy. ,"Multimerization assay performed with the Cys2773Arg recombinant mutant and wt vWF expressed by COS7 cells showed abnormal multimers, including loss of HMWM and an extra central band, indicating that this variant has a damaging effect on protein function. Additionally, collagen binding was disrupted. (PMID: 11264172 Fig. 5; PS3) Similar results were also reported in PMID:24598842.
","Multimerization assay performed with the Cys2773Arg recombinant mutant and wt vWF expressed by COS7 cells showed abnormal multimers, including loss of HMWM and an extra central band, indicating that this variant has a damaging effect on protein function. Additionally, collagen binding was disrupted. (PMID: 11264172 Fig. 5; PS3) Similar results were also reported in PMID:24598842.
 Found similar defects in dimerization using atomic force microscopy. ",ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
8386,NM_000249.4(MLH1):c.649C>T (p.Arg217Cys),MLH1,Lynch syndrome 1,MONDO:0007356,Benign,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,BS3,met,PubMed:32849802,CIMRA Functional Odds for Pathogenicity is  0.01 (Data_Sheet_1),CIMRA Functional Odds for Pathogenicity is  0.01 which is below the VCEP threshold of ≤ 0.052,CIMRA Functional Odds for Pathogenicity is  0.01 which is below the VCEP threshold of ≤ 0.052 CIMRA Functional Odds for Pathogenicity is  0.01 (Data_Sheet_1),ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMLH1Version1.0.0_version=1.0.0.csv
8400,NM_000251.3(MSH2):c.1012G>A (p.Gly338Arg),MSH2,Lynch syndrome,MONDO:0005835,Pathogenic,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,PS3,met,PubMed:32849802,Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7)  Data_Sheet_1,Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7),Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7) Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7)  Data_Sheet_1,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH2Version1.0.0_version=1.0.0.csv
8403,NM_000251.3(MSH2):c.2075G>T (p.Gly692Val),MSH2,Lynch syndrome 1,MONDO:0007356,Pathogenic,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,PS3,met,PubMed:32849802,The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3).   Data_Sheet_1,The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3).,The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3). The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3).   Data_Sheet_1,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH2Version1.0.0_version=1.0.0.csv
8408,NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del),MSH6,Lynch syndrome,MONDO:0005835,Likely Pathogenic,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,PS3,met,PubMed:31965077,CIMRA has shown a relative repair compared to wild type (WT) = 7.0% (corresponds to odds of ~43),CIMRA has shown a relative repair compared to wild type (WT) = 7.0% (corresponds to odds of ~43),CIMRA has shown a relative repair compared to wild type (WT) = 7.0% (corresponds to odds of ~43) CIMRA has shown a relative repair compared to wild type (WT) = 7.0% (corresponds to odds of ~43),ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH6Version1.0.0_version=1.0.0.csv
8410,NM_000179.3(MSH6):c.1296T>G (p.Phe432Leu),MSH6,Lynch syndrome,MONDO:0005835,Likely Pathogenic,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,PS3,met,PubMed:31965077,Supplementary material. Table S5: p.F432L CIMRA functional odds: 45.743 ,Functional odds: 45.743 (CIMRA Functional Odds for Pathogenicity >18.7),Functional odds: 45.743 (CIMRA Functional Odds for Pathogenicity >18.7) Supplementary material. Table S5: p.F432L CIMRA functional odds: 45.743 ,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH6Version1.0.0_version=1.0.0.csv
8702,NM_000552.5:c.4586_4591del,VWF,von Willebrand disease type 2A,MONDO:0015628,Pathogenic,Autosomal dominant inheritance,von Willebrand Disease,2024-11-06,PS3,met,PubMed:22479377,"Multimerization assay performed with the Asp1529_Val1530del recombinant mutant vWF expressed by HEK293 showed abnormal multimers with less HMW multimers (consistent with the multimer assay in the patient), indicating that this variant has a damaging effect on protein function (PMID:22479377; PS3).

Immunofluorescence indicated that a significant portion of the mutant VWF molecules were retained in the ER.","Multimerization assay performed with the Asp1529_Val1530del recombinant mutant vWF expressed by HEK293 showed abnormal multimers with less HMW multimers, indicating that this variant has a damaging effect on protein function (PMID:22479377; PS3).","Multimerization assay performed with the Asp1529_Val1530del recombinant mutant vWF expressed by HEK293 showed abnormal multimers with less HMW multimers, indicating that this variant has a damaging effect on protein function (PMID:22479377; PS3). Multimerization assay performed with the Asp1529_Val1530del recombinant mutant vWF expressed by HEK293 showed abnormal multimers with less HMW multimers (consistent with the multimer assay in the patient), indicating that this variant has a damaging effect on protein function (PMID:22479377; PS3).

Immunofluorescence indicated that a significant portion of the mutant VWF molecules were retained in the ER.",ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
9137,NM_001130987.2(DYSF):c.1906G>C (p.Gly636Arg),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3,met,PubMed:35028538,"Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). ","Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). 
","Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). 
 Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). ",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9156,NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3,met,PubMed:23185377,"membrane resealing activity assay, which is not considered an acceptable assay for PS3 but is consistent with mouse model data","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3)","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3) membrane resealing activity assay, which is not considered an acceptable assay for PS3 but is consistent with mouse model data",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9156,NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3,met,PubMed:30292141,"Generated a new mouse model (MMex38) carrying a missense mutation in exon 38 in analogy to a clinically relevant human DYSF variant (DYSF p.Leu1341Pro). The targeted mutation induces all characteristics of missense mutant dysferlinopathy, including a progressive dystrophic pattern, amyloid formation, and defects in membrane repair. Homozygous mutant newborn mice clinically and histopathologically do not display symptoms (data not shown). Signs of muscular dystrophy, such as necrotic and regenerating muscle fibers, fiber splitting, and fibrosis, first occurred in early adulthood (from week 12 onward) (Figure 1C; quantification and statistics are demonstrated in Figure S2), and they progressed significantly with age. At 60 months of age, more muscle fibers were replaced by fatty fibrosis (Figure 1C). On protein level Dysf p.Leu1360Pro led to a 90% reduction of dysferlin as assessed by western blot. Immunofluorescence stain for dysferlin on a frozen section revealed the absence of mutant dysferlin at the sarcolemma but occasional accumulations (Figure 1B). As described for the patients carrying DYSF missense mutations, MMex38 mouse muscle also displayed amyloid deposits at vessel walls (Figure 1D) and at the sarcolemma at older age. To assess dysferlin function in MMex38 mouse muscle, we performed the laser-wounding assay on isolated muscle fibers from MMex38 flexor digitorum brevis muscle ex vivo. Membrane repair was significantly delayed in MMex38 as compared to wild-type (WT) littermates (Figure 1E).
discussed with VCEP and agreed to score as PS3_Strong","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3)","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3) Generated a new mouse model (MMex38) carrying a missense mutation in exon 38 in analogy to a clinically relevant human DYSF variant (DYSF p.Leu1341Pro). The targeted mutation induces all characteristics of missense mutant dysferlinopathy, including a progressive dystrophic pattern, amyloid formation, and defects in membrane repair. Homozygous mutant newborn mice clinically and histopathologically do not display symptoms (data not shown). Signs of muscular dystrophy, such as necrotic and regenerating muscle fibers, fiber splitting, and fibrosis, first occurred in early adulthood (from week 12 onward) (Figure 1C; quantification and statistics are demonstrated in Figure S2), and they progressed significantly with age. At 60 months of age, more muscle fibers were replaced by fatty fibrosis (Figure 1C). On protein level Dysf p.Leu1360Pro led to a 90% reduction of dysferlin as assessed by western blot. Immunofluorescence stain for dysferlin on a frozen section revealed the absence of mutant dysferlin at the sarcolemma but occasional accumulations (Figure 1B). As described for the patients carrying DYSF missense mutations, MMex38 mouse muscle also displayed amyloid deposits at vessel walls (Figure 1D) and at the sarcolemma at older age. To assess dysferlin function in MMex38 mouse muscle, we performed the laser-wounding assay on isolated muscle fibers from MMex38 flexor digitorum brevis muscle ex vivo. Membrane repair was significantly delayed in MMex38 as compared to wild-type (WT) littermates (Figure 1E).
discussed with VCEP and agreed to score as PS3_Strong",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9156,NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3,met,PubMed:35028538,"Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3)","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3) Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9559,NM_000180.4(GUCY2D):c.1371C>T (p.Cys457=),GUCY2D,GUCY2D-related recessive retinopathy,MONDO:0100453,Benign,Autosomal recessive inheritance,Leber Congenital Amaurosis/early onset Retinal Dystrophy,2025-01-30,BA1,met,PubMed:18682808,"Seong, et al, 2008, tested 20 Korean patients diagnosed with LCA and 170 control patients. GUCY2D cys457= is listed as a polymorphic variant and had an allele frequency of 0.75 in 170 controls tested.","This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.1129, with 5137 alleles/44460 total alleles and 134 homozygotes in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.008. (BA1).","This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.1129, with 5137 alleles/44460 total alleles and 134 homozygotes in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.008. (BA1). Seong, et al, 2008, tested 20 Korean patients diagnosed with LCA and 170 control patients. GUCY2D cys457= is listed as a polymorphic variant and had an allele frequency of 0.75 in 170 controls tested.",ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv