ClinVar

Description

Variant summary: HNF1A c.521C>T (p.Ala174Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 250584 control chromosomes in GnomAD. The observed variant frequency is approximately 8.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), strongly suggesting that the variant is benign. c.521C>T has been reported in the literature in individuals affected with features of Maturity Onset Diabetes Of The Young without strong evidence for causality (example: Bellann-Chantelot_2007, Furuzawa_2008, Colclough_2022, Bonnefond_2020). These reports do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18003757, 33046911, 34789499, 18672310, 33729509). Two clinical diagnostic laboratories have submitted clinical-significance assessments (likely benign and uncertain significance, respectively) for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign.