The c.779C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 260 (p.(Thr260Met)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 28 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 30760653, 29927023, 30663027, 29207974, 28105082, internal lab contributors). At least two of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A, and both were antibody negative and one responded to low dose sulfonylureas) (PP4_Moderate; PMIDs: 30760653, 281505082). This variant segregated with diabetes, with 16 informative meioses in multiple families with MODY (PP1_Strong; PMIDs: 30760653. 28105082, internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Thr260Met protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate; PMID: 32910913). In summary, c.779C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_supporting, PM2_Supporting, PP3, PS4, PP4_Moderate, PP1_Strong, PS3_Moderate.