ClinVar

Description

The c.113A>T variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to leucine at codon 38 (p.(Gln38Leu)) 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 has a REVEL score of 0.657, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. 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 OGTT increment < 3 mmol/L) (PP4_Moderate; PMID: 24550216, internal lab contributors). This variant segregated with hyperglycemia with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 24550216, internal lab contributors). Another missense variant, c.113A>C p.Gln38Pro, has been interpreted as pathogenic by the ClinGen MDEP, and p.Gln38Leu has a greater Grantham distance (PM5). In summary, c.113A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM5, PP2, PM2_Supporting.