The c.358A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamic acid at codon 120 (p.(Lys120Glu)) 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). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This is supported by functional studies that demonstrated the p.Lys120Glu protein has DNA binding and transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 32017842). Additionally, 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 (PS4_Moderate; PMID: 24698406, PMID: 32741144, internal lab contributor). At least one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 24698406). In summary, the c.358A>G 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 2.0.0, approved 1/22/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PS3_Supporting.