The c.682dup variant in the HNF1 homebox A gene, HNF1A, causes a frameshift in the protein at codon 228 (NM_000545.8), adding 11 novel amino acids before encountering a stop codon (p.(Glu228GlyfsTer11)). This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant 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:18003757, internal lab contributor). One of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4Al, and negative antibodies) (PP4; 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 (PMID: 27236918, internal lab contributor). In summary, c.682dup meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PP4_Moderate, PM2_Supporting.