ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.626C>T (p.Thr209Met)

dbSNP: rs1583599303
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000992057 SCV001144026 pathogenic not provided 2019-06-28 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/282820 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism.
Invitae RCV000992057 SCV002239107 pathogenic not provided 2023-07-28 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 209 of the GCK protein (p.Thr209Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hyperinsulinemic hypoglycemia (PMID: 8168652, 23352578, 25174781, 28371533). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 804851). 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. Experimental studies have shown that this missense change affects GCK function (PMID: 10426385). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265919 SCV002547878 pathogenic Monogenic diabetes 2022-05-12 criteria provided, single submitter clinical testing Variant summary: GCK c.626C>T (p.Thr209Met) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain 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 251450 control chromosomes. c.626C>T has been reported in the literature in multiple individuals affected with Monogenic Diabetes, including at least one case where the variant was found to be de novo (Estalella_2007, Codner_2009, Bennett_2015, Gaal_2021). These data indicate that the variant is very likely to be associated with disease. Two 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002354899 SCV002605193 likely risk allele Maturity onset diabetes mellitus in young criteria provided, single submitter research Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1583599303 in MODY, yet.
Ambry Genetics RCV002354899 SCV002655881 likely pathogenic Maturity onset diabetes mellitus in young 2017-07-26 criteria provided, single submitter clinical testing The p.T209M variant (also known as c.626C>T), located in coding exon 6 of the GCK gene, results from a C to T substitution at nucleotide position 626. The threonine at codon 209 is replaced by methionine, an amino acid with similar properties. This variant was identified in multiple maturity-onset diabetes of the young families (Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26; Alkorta-Aranburu G et al. Mol. Genet. Metab., 2014 Dec;113:315-20). 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.

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