The c.1340_1368del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 2 novel amino acids before encountering a stop codon (p.(Arg447LeufsTer2)). 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 from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 16 unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Additionally, this variant segregated with diabetes/hyperglycemia with 8 informative meioses in one family with MODY (PP1_Strong; internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMP/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP1_Strong, PS4, PP4, PM2_Supporting).