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

dbSNP: rs193922336

Total submissions: 4

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	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.
Labcorp Genetics (formerly Invitae), Labcorp	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.