GCK p.Phe152Ser

The c.455T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 152 (p.(Phe152Ser)) 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 0.981, 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 clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibody) (PP4_Moderate; PMID: 21978167). This variant segregated with diabetes/hyperglycemia, with four informative meioses in two families (PP1_Strong; PMID: 21978167, internal lab contributors]). Another missense variant, c.454T>C p.(Phe152Leu)​ has been interpreted as pathogenic by the ClinGen MDEP, and p.(Phe152Ser)​ has an equal or greater Grantham distance (PM5). In summary, c.455T>C meets the criteria to be classified as a variant of pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP2, PM5, PP4_Moderate, PP1_Strong.