ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.907C>T (p.Arg303Trp)

dbSNP: rs193922336
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029927 SCV000052582 likely pathogenic Maturity-onset diabetes of the young type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Athena Diagnostics Inc RCV000711788 SCV000842185 likely pathogenic not provided 2018-01-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV002371788 SCV002688544 likely pathogenic Maturity onset diabetes mellitus in young 2017-03-07 criteria provided, single submitter clinical testing The p.R303W variant (also known as c.907C>T), located in coding exon 8 of the GCK gene, results from a C to T substitution at nucleotide position 907. The arginine at codon 303 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in multiple individual's with a clinical diagnosis of MODY (Codner E et al. Diabetes Metab. Res. Rev.;22:348-55; Capuano M et al. PLoS ONE, 2012 Jun;7:e38906). Functional analysis has shown this variant results in significantly reduced enzyme activity compared to wild-type (p<0.05) (Capuano M et al. PLoS ONE, 2012 Jun;7:e38906). 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.
Invitae RCV000711788 SCV004295150 likely pathogenic not provided 2023-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 303 of the GCK protein (p.Arg303Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 16444761, 22761713). ClinVar contains an entry for this variant (Variation ID: 36264). 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: 22761713, 29704611). This variant disrupts the p.Arg303 amino acid residue in GCK. Other variant(s) that disrupt this residue have been observed in individuals with GCK-related conditions (PMID: 25921421, 30259503, 31063852), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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