owencqueen/cgbench_data huggingface dataset:
Gene: HNF1A (HGNC:11621)
Evidence Code: PS1 — Strong
Modification Type: No change
No change
Gene: HNF1A (HGNC:11621)
Evidence Code: PS2 — Very Strong
Modification Type: Gene-specific,Strength
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described below.
Gene: HNF1A (HGNC:11621)
Evidence Code: PS2 — Strong
Modification Type: Gene-specific,Strength
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described below.
Gene: HNF1A (HGNC:11621)
Evidence Code: PS2 — Moderate
Modification Type: Gene-specific,Strength
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described below.
Gene: HNF1A (HGNC:11621)
Evidence Code: PS2 — Supporting
Modification Type: Gene-specific,Strength
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described below.
Gene: HNF1A (HGNC:11621)
Evidence Code: PS3 — Moderate
Modification Type: Gene-specific,Strength
Applicable for variants with luciferase assay data (evidence of decreased transactivation (<=40% of wild type) by the Gloyn/Oxford group (Althari et al, (2020) (DOI: 
https://doi.org/10.1016/j.ajhg.2020.08.016
 (DOI: 
https://doi.org/10.1016/j.ajhg.2020.08.016
).)).
Gene: HNF1A (HGNC:11621)
Evidence Code: PS4 — Strong
Modification Type: Gene-specific,Strength
Seven or more= Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).




Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.


 4-6 unrelated occurrences = Moderate, 7 or more = Strong






Phenotype of the affected individual must include diabetes, with evidence of an autoimmune etiology and/or absolute or near-absolute insulin deficiency considered exclusionary (see above).


 Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region).


 References


McDonald et al (2011) (PMID: 21395678)


Shields et al (2017) (PMID: 28701371)


Patel et al (2019) (PMID: 30409810)
Gene: HNF1A (HGNC:11621)
Evidence Code: PS4 — Moderate
Modification Type: Gene-specific,Strength
4-6 unrelated occurrences = Moderate. Variant should meet PM2_Supporting in order to use PS4 at any level. Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).
Gene: HNF1A (HGNC:11621)
Evidence Code: PM1 — Moderate
Modification Type: Gene-specific,Strength
This criterion can be used for variants in residues that directly bind DNA (see below).


PM1: Applicable to amino acids that directly bind DNA (PMID: 12453420)
o Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273
Gene: HNF1A (HGNC:11621)
Evidence Code: PM1 — Supporting
Modification Type: Gene-specific,Strength
Use for defined regions in the DNA binding and dimerization domains. It can also be used for variants within certain transcription factor binding sites of the promoter.


PM1_Supporting: Applicable for SNV and non-frameshift indel variants in the promoter, DNA binding and dimerization domains (PMID: 18003757)  




Promoter 


–c.-187 to c.-195 (AP1 binding site) 


–c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites) 


–c.-238 to c.-259 (HNF1A binding site) 


–c.-276 to c.-288 (HNF4A binding site)






Dimerization: codons 1-32, NM_000545.8


Subset of DNA binding domains: codons 107-174 and 201-280, NM_000545.8
Gene: HNF1A (HGNC:11621)
Evidence Code: PM2 — Supporting
Modification Type: General recommendation,Gene-specific
Prevalence ≤ 1:50,000 (≤ 0.00002 or 0.002%) in gnomAD European Non-Finnish population AND ≤ 1 copy in other founder and non-founder populations (would require ≤ 1/50,000 in non-European populations if/when they surpass 100,000 alleles).
Gene: HNF1A (HGNC:11621)
Evidence Code: PP1 — Strong
Modification Type: General recommendation,Gene-specific
Use thresholds suggested by Jarvik and Browning (PMID: 27236918)




Single Family : ≤ 1/32 (5 meioses)


1 Family : ≤ 1/16 (4 meioses)
Gene: HNF1A (HGNC:11621)
Evidence Code: PP1 — Moderate
Modification Type: General recommendation,Gene-specific
Use thresholds suggested by Jarvik and Browning (PMID: 27236918)




Single Family : ≤ 1/16 (4 meioses)


1 Family : ≤ 1/8 (3 meioses)
Gene: HNF1A (HGNC:11621)
Evidence Code: PP1 — Supporting
Modification Type: General recommendation,Gene-specific
Use thresholds suggested by Jarvik and Browning (PMID: 27236918)




Single Family : ≤ 1/8 (3 meioses)


1 Family : ≤ ¼ (2 meioses)
Gene: HNF1A (HGNC:11621)
Evidence Code: PP4 — Moderate
Modification Type: Gene-specific
MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
https://www.diabetesgenes.org/mody-probability-calculator/
) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:




Antibody negative and/or persistent C-peptide after five years post- T1DM diagnosis


Response to low-dose SU (extreme response- hypoglycemia)


Low hsCRP in patient with clinical diagnosis of T2DM


Biochemical/Molecular phenotypic evidence from patient cell lines


Hepatocellular adenomas
Gene: HNF1A (HGNC:11621)
Evidence Code: PP4 — Supporting
Modification Type: Gene-specific
MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
https://www.diabetesgenes.org/mody-probability-calculator/
) AND negative HNF4A testing
Gene: HNF1A (HGNC:11621)
Evidence Code: BS2 — Strong
Modification Type: Gene-specific
Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative).
Gene: HNF1A (HGNC:11621)
Evidence Code: BS3 — Strong
Modification Type: Gene-specific
Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.
Gene: HNF1A (HGNC:11621)
Evidence Code: BS3 — Supporting
Modification Type: Gene-specific
See list of approved functional studies and guidelines for interpretation of data.




Luciferase assays for transactivation


“No functional impact” is defined as ≥75% activity of wildtype. If data from more than one experiment is available, do not apply BS3_Supporting if one result is ≥75% and the other is not.


Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depending on many factors, for instance cell line used (HeLa, INS, MIN6 etc). Please see PS3_Supporting section above for recommendations on controls. The degree of TA impairment of HNF1A tends to correlate positively with severity of phenotype: that is MODY causal HNF1A variants impair TA activity more severely (<40% compared to WT) than T2D risk variants (40-75% compared to WT).






EMSA for DNA binding


“No functional impact” is defined as ≥75% activity of wildtype.


Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain. Please see PS3_Supporting section above for recommendations on controls.






Western blotting and indirect immunofluorescence for protein expression & localization


Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Sample preparations, gel loading, transfer efficiency, antibody specificity, choice of internal control and quantification method are some of the factors that can contribute to varying and inconsistent results between labs. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3.






References


Najmi et al (2017) (PMID: 27899486)


Bjorkhaug et al (2003) (PMID: 12574234)


Brnich et al (2020) (PMID: 31892348)


Althari et al (2020) (PMID: 32910913)
Gene: HNF1A (HGNC:11621)
Evidence Code: BP7 — Supporting
Modification Type: General recommendation
Use with no specifications.