ClinVar

Description

The p.Arg131Gln variant in HNF1A has been reported in at least 15 individuals with maturity-onset diabetes of the young, segregated with disease in 4 affected relatives from 2 families (PMID: 24323243, 12442280, 22060211, 17937063, 18838325, 11315851, 9032114, 9287053, 18003757), but has been identified in 0.0009% (1/113698) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753998395). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic by Columbia University in ClinVar (Variation ID: 562373). In vitro functional studies provide some evidence that the p.Arg131Gln variant may slightly impact protein function (PMID: 27899486). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg131Gln variant is located in a region of HNF1A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 28410371). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on more affected individuals with the variant than expected, low frequency in the general population, location in a functional domain, and in vitro functional studies. ACMG/AMP Criteria applied: PS4, PM2, PM1, PP3, PP1, PS3_Supporting (Richards 2015).