ClinVar

Description

The c.35T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to arginine at codon 12 (p.(Leu12Arg)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9409, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in multiple individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to sulfonylurea) (PP4_Moderate; internal lab contributors). Lastly, another missense variant, c.34C>G, (p.Leu12Val), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, PM1_Supporting, PP3, PP4_Moderate, PM5_Supporting.