ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.571C>T (p.Arg191Trp) (rs1085307455)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000490143 SCV000613442 pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing
GeneDx RCV000490143 SCV000576488 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing The R191W variant has been published previously in association with MODY (Vits et al., 2006; Sagen et al., 2008; Caetano et al., 2012). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R191W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the hexokinase small domain that is conserved across species; the small domain is a hotspot for GCK variants (Tinto et al., 2008). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (R191L/Q) and in nearby residues (R186G/Q, D187Y, A188P/T/V, I189T, R192S, G193W/R) have been reported in the Human Gene Mutation Database in association with diabetes and MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
Translational Genomics Laboratory,University of Maryland School of Medicine RCV000754816 SCV000882466 pathogenic Maturity-onset diabetes of the young, type 2 2017-11-07 criteria provided, single submitter clinical testing The c.571C>T variant in codon 191 (exon 6) of the glucokinase gene, GCK, results in the substitution of Arginine to Tryptophan. Missense mutations in GCK, including ones in exon 6, have been reported in patients with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (19790256). The c.571C>T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the c.571C>T variant was previously identified in individuals with a MODY2 phenotype of Korean, Norwegian, Belgian, Brazilian, French, Japanese, Italian, and British descent (16632067, 18399931, 16965331, 23295292, 18411240, 22060211, 11508276, 10753050) . Other amino acid substitutions at this residue, p.Arg191Gln and p.Arg191Leu, have been found in individuals with a MODY2 phenotype (19790256, 11508276, 16444761, 19309449). Additionally, multiple lines of computational evidence (LRT, MutationTaster, FATHMM, MetaSVM, MetalR, Provean, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. The c.571C>T variant is located within the small domain of the protein, a region considered to be a mutational hotspot (18382660). ACMG criteria = PS4, PM1, PM2, PP1-mod, PP3

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