ClinVar

Description

The c.260G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to asparagine at codon 120 (p.(Lys120Asn)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.8169, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributor). The c.260G>C variant was found in an an infant with diabetes attributed to a de novo pathogenic INS variant. The age of the child and INS variant precluded deriving evidence in support of or against an impact of the HNF1A variant, which is generally expected to manifest at or near puberty. Notably, the HNF1A variant was inherited from the father, who had a clinical presentation consistent with HNF1A-monogenic diabetes. Finally, another missense variant, c.358A>G (p.Lys120Glu), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.360G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting.