The c.1346_1362del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 449 (NM_000162.5), adding 4 novel amino acids before encountering a stop codon (p.(Ala449GlyfsTer4)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent in gnomAD (PM2_Supporting). This variant was identified in 5 unrelated individuals with a clinical picture consistent with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in at least two individuals with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4_Moderate, internal lab contributors). This variant segregated with disease with 2 informative meioses in 2 families with MODY (PP1; internal lab contributors). In summary, the c.1346_1362del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP4, PS4_Moderate, PP1, PM2_Supporting.