The c.1121T>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to glutamic acid at codon 374 (p.(Val374Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.968, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1120G>A p.(Val374Met), has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). This variant was identified in two unrelated individuals with hypglycemia; however, this number does not meet the MDEP cutoff for PS4_Moderate (Solano et al. 2019. Rev Esp Endocrinol Pediatr 10(2):69-73, internal lab contributors). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Supporting .