ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.425C>T (p.Ser142Phe)

dbSNP: rs2135832668
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV001794564 SCV002032364 pathogenic Monogenic diabetes 2021-08-24 reviewed by expert panel curation The c.425C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to phenylalanine at codon 142 (p.(Ser142Phe)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This is supported by functional studies that demonstrated the p.Ser142Phe protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting, PMID: 10585442). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.977, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 9 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 31968686, PMID 9097962, PMID: 23610083, PMID: 21224407, internal lab contributors). This variant segregated with diabetes, with 14 informative meioses in 5 families with MODY (PP1_Strong; PMID 31968686, PMID 9097962, internal lab contributors). This variant was identified in an individual with diabetes with a calculated MODY probability of <50%, however the presence of a moderate level of criteria (persistent C-peptide) allows the application of this criteria at a supporting level per the ClinGen MDEP's approval (PP4; PMID 31968686). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied (specification version 1.0, approved 8/24/21): PP1_Strong, PS4, PP3, PP4, PM1_Supporting, PM2_Supporting, PS3_Supporting.
Revvity Omics, Revvity RCV003136157 SCV003822784 pathogenic not provided 2022-03-03 criteria provided, single submitter clinical testing

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