The c.364C>G variant in the glucokinase gene, GCK, causes an amino acid change of leucine to valine at codon 122 (p.(Leu122Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 11508276, 32468610, internal lab contributors). Two of these individuals and one relative had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 32468610, internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1; PMIDs: 32468610). Another missense variant, c.364C>T, p.Leu122Phe, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Taken together, this evidence supports the classification of c.364C>G as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Moderate, PM5_Supporting, PM2_Supporting, PP2, PP3, PP4.