ClinVar Genomic variation as it relates to human health

The c.502A>C variant in the glucokinase gene, GCK causes an amino acid change of The to Pro at codon 168 (p.(Thr168Pro)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.988, 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 4 unrelated individuals with diabetes (PS4_Moderate; 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 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 5 informative meioses in 3 families with diabetes (PP1_Strong; PMID:9049484, internal lab contributors). This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, but the wild-type ATP Km is not between 0.4-0.65, and the p.Gly175Arg has Kcat/S0.5<0.5 (PS3_Supporting; PMID 10525657). The c.502A>G, p.Thr168Ala and c.503C>A, p.Thr168Asn variants have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, this variant meets the criteria to be classified as Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PP2, PM1, PP3, PS3_Supporting, PP1_Strong, PM5_Strong, PS4_Moderate, PP4_Moderate.