ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.184G>A (p.Val62Met) (rs1064793998)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481874 SCV000567543 pathogenic not provided 2015-08-07 criteria provided, single submitter clinical testing The V62M missense variant in the GCK gene has been reported previously in associationwith maturity-onset diabetes of the young type 2 (MODY2), or GCK-MODY (Gloyn et al.,2005). Additionally, multiple functional studies predict lowered catalytic levels, decreasedthermal stability, or reduced interaction with regulatory proteins due to this missensechange (Arden et al., 2007; Ralph et al., 2009; Zelent et al., 2011). Therefore, we consider V62M to be a pathogenic variant.
Athena Diagnostics Inc RCV000481874 SCV000613416 pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing
Translational Genomics Laboratory,University of Maryland School of Medicine RCV000754817 SCV000882467 pathogenic Maturity-onset diabetes of the young, type 2 2018-03-12 criteria provided, single submitter clinical testing The c.184G>A variant in codon 62 (exon 3 of the RefSeqGene and of NM_000162.3) of the glucokinase gene, GCK, results in the substitution of Valine to Methionine. Missense mutations in GCK, including ones in this exon, have been reported in patients with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (19790256). The c.184G>A variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the c.184G>A variant was previously shown to segregate with elevated fasting plasma glucose in three families (15677479, 27271189), A different amino acid substitution at this residue, p.Val62Ala, was shown to segregate with diabetes and impaired glucose tolerance in multiple individuals across four generations in a Norwegian family (9736233, 18399931). Additionally, multiple lines of computational evidence (MutationTaster, FATHMM, MetaSVM, MetalR, Provean, LRT, SIFT, Polyphen, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. Indeed, functional studies have demonstrated impaired enzyme activity of both the p.Val62Met and p.Val62Ala mutant proteins (15677479, 16731834, 17389332, 19187021). ACMG criteria = PP1strong, PS4mod, PS3, PM2, PP3

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