ClinVar Genomic variation as it relates to human health

The c.110T>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 37 (p.(Met37Lys)) 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 0.9549, 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 phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). Another missense variant, c.110T>G p.Met37Arg, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met37Lys has a greater Grantham distance (PM5). In summary, c.110T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5, PP2, PP3, PM2_Supporting.