ClinVar Genomic variation as it relates to human health

The c.524G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to glutamate at codon 175 (p.(Gly175Glu)) 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 0.914, 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 four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 11508276, internal lab contributors). This variant was identified as a de novo occurrence with unconfirmed parental relationships in one individual with a clinical picture consistent with GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6) (PS2_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%) (PP4; internal lab contributors). Another missense variant, c.523G>A p.Gly175Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly175Glu (PM5_Supporting). In summary, c.524G>A 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): PS4_Moderate, PS2_Moderate, PP4, PM2_Supporting, PP2, PP3, PM5_Supporting.

The p.G175E variant (also known as c.524G>A), located in coding exon 5 of the GCK gene, results from a G to A substitution at nucleotide position 524. The glycine at codon 175 is replaced by glutamic acid, an amino acid with similar properties. This alteration was detected in an Italian pediatric patient meeting diagnostic criteria for MODY (Massa O et al. Diabetologia, 2001 Jul;44:898-905). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Hinklin RJ et al. J Med Chem, 2014 Oct;57:8180-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.