ClinVar Genomic variation as it relates to human health

The c.523G>A variant in the glucokinase gene, GCK causes an amino acid change of Gly to Arg at codon 210 (p.(Gly175Arg)) 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 0.965, 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 8 unrelated individuals with diabetes (PS4; PMID: 29944009, 20337973, 26552609, 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 three-generation, dominant family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 5 informative meioses in 4 families with diabetes (PP1_Strong; internal lab contributors). 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 variant has Kcat/S0.5<0.5 (PS3_Supporting; PMID 10525657). The nucleotide change c.523G>C, which causes the same amino acid change, has been classified as pathogenic for MODY by the ClinGen MDEP (PS1). 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) : PS4, PP1_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, PP2, PP3, PS1.

The p.G175R variant (also known as c.523G>A), located in coding exon 5 of the GCK gene, results from a G to A substitution at nucleotide position 523. The glycine at codon 175 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with a clinical history consistent with or suspicious for GCK-MODY (Froguel P et al. N Engl J Med, 1993 Mar;328:697-702; Pruhova S et al. Pediatr Diabetes, 2010 Dec;11:529-35; Gozlan Y et al. Pediatr Diabetes, 2012 Sep;13:e14-21; Lunt H et al. J Diabetes Sci Technol, 2018 11;12:1248-1249) and has been shown to segregate with disease (Ambry internal data). This variant results in reduced glucokinase activity (Liang Y et al. Biochem J, 1995 Jul;309 ( Pt 1):167-73; Gidh-Jain M et al. Proc Natl Acad Sci U S A, 1993 Mar;90:1932-6; Davis EA et al. Diabetologia, 1999 Oct;42:1175-86). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Variant summary: GCK c.523G>A (p.Gly175Arg) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250998 control chromosomes (gnomAD). c.523G>A has been reported in the literature in multiple individuals affected with maturity-onset diabetes of the young type 2 (Martin_2008, Pruhova_2010). These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function and this variant results in low expressed protein level and enzymatic activity (Gidh-Jain_1993, Davis_1999). The following publications have been ascertained in the context of this evaluation (PMID: 8433729, 8068341, 10525657, 8446612, 18411240, 20337973). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as pathogenic (classified by ClinGen Monogenic Diabetes Variant Curation Expert Panel) and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.