ClinVar

Description

The c.695T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 232 (p.(Leu232Pro)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is also 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). Additionally, functional studies demonstrated the p.Leu232Pro protein has DNA binding and transactivation below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting, internal lab contributor). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 29875428, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, treated with low-dose sulfonylureas, and persistent C-peptide) (PP4_Moderate; internal lab contributor). This variant also segregated with diabetes/hepatic adenomas, with three informative meioses in two families (PP1_Moderate; PMID: 29875428, internal lab contributors). In summary, the c.695T>C 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 2.1.0, approved 8/11/2023): PP1_Moderate, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting, PS3_Supporting.