ClinVar

Description

The c.391C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 131 (p.(R131W)) of NM_000545.8. 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). and is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.392G>A (p.Arg131Gln) has been interpreted as pathogenic by the ClinGen MDEP and p.Arg131Trp has an equal or greater Grantham distance. (PM5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 44 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9166684, PMID:9075818, PMID:22060211, internal lab contributors). However, the MODY probability is unable to be calculated due to lack of clinical information (PMID:9166684, PMID:9075818, PMID:22060211 internal lab contributors). This variant segregated with disease with 11 informative meioses in six families with MODY (PP1_Strong, internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_Strong, PS4, PM1, PM5, PP3, PM2_Supporting).