ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.617C>T (p.Thr206Met)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001553149 SCV001773965 pathogenic not provided 2021-10-27 criteria provided, single submitter clinical testing 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)
Genetic Services Laboratory,University of Chicago RCV001553149 SCV002072031 likely pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing 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).
Invitae RCV001553149 SCV002179995 pathogenic not provided 2021-10-05 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 206 of the GCK protein (p.Thr206Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with autosomal dominant maturity-onset diabetes of the young (MODY) (PMID: 11508276, 15928245, 16173921, 31216263). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this variant affects GCK protein function (PMID: 16173921). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271659 SCV002555833 pathogenic Monogenic diabetes 2022-06-11 criteria provided, single submitter clinical testing 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.

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