The c.779C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to lysine at codon 260 (p.(Thr260Lys)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two 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 (internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result nearly 50%, negative genetic testing for HNF4A, and negative antibodies). While the MODY probability score was slightly below 50%, the patient was on insulin with a C-peptide in the normal range and thus the score was likely an underestimate, and clinical judgment was used to apply PP4_Moderate (internal lab contributors). Another missense variant, c.779C>T p.Thr260Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr260Lys (PM5_Supporting). In summary, c.779C>A 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.