The c.898G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 300 (p.(Glu300Lys)) 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 0.977, 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 three unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 8433729, 22035297, internal lab contributors). 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.898G>C p.(Glu300Gln), has been classified as pathogenic by the ClinGen MDEP VCEP and has a lower Grantham distance than p.(Glu300Lys) (PM5). While the relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, the variant was shown through a cellular assay to be unstable (PS3_Supporting; PMIDs: 10455021, 10525657, https://doi.org/10.1159/000079009). 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 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5, PS3_Supporting.