ClinVar Genomic variation as it relates to human health

DNA sequence analysis of the GCK gene demonstrated a sequence change, c.617C>T, in exon 6 that results in an amino acid change, p.Thr206Met. The p.Thr206Met change affects a highly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. The p.Thr206Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Thr206Met sequence change has previously been described in multiple patients with GCK-related maturity onset diabetes of the young (MODY) (PMIDs: 24606082, 2014, 11508276). Several other pathogenic sequence changes affecting the same p.Thr206 amino acid (p.Thr206Arg, p.Thr206Lys, p.Thr206Ala, and p.Thr206Pro) have been reported in patients with GCK-MODY (PMIDs: 19790256, 17937063, 12442280, 24405491). Furthermore, functional studies of the p.Thr206Met sequence change demonstrated that it results in severe loss of function (PMID: 24606082).

Variant summary: GCK c.617C>T (p.Thr206Met) 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 allele was found at a frequency of 4e-06 in 251436 control chromosomes. c.617C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young (example, Galan_2006, Kavvoura_2014, Aloi_2017, Gaal_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Galan_2006). The most pronounced variant effect results in lowered substrate affinity for glucose indicating a loss of cooperativity for glucose as a substrate and a severely diminished catalytic constant. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Published functional studies demonstrate a damaging effect, specifically enzymatic assays reveal an activity index corresponding to 0.2% of wildtype GK activity (Galn et al., 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 11508276, 12955723, 15841481, 16173921, 29927023, 29056535, 28726111, 28170077, 31216263)

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 206 of the GCK protein (p.Thr206Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (MODY) (PMID: 11508276, 15928245, 16173921, 31216263). ClinVar contains an entry for this variant (Variation ID: 1191898). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GCK protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 16173921). For these reasons, this variant has been classified as Pathogenic.

GCK: PM1, PM2, PM5, PS4:Moderate, PP3, PP4, PS3:Supporting