ClinVar Genomic variation as it relates to human health

The c.110T>G variant in the glucokinase gene,GCK, causes an amino acid change of methionine to arginine at codon 37 (p.(Met37Arg)) of NM_000162.5. This variant segregated with diabetes, with at least four informative meioses in two families with MODY (PP1_Strong; 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% and an OGTT with minimal increment) (PP4_Moderate; internal lab contributor). This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributor, DOI: 10.1055/s-2008-1004713). 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 0.9739, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.110T>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting.