ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.731T>A (p.Val244Glu)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002380105 SCV002668463 likely pathogenic Maturity onset diabetes mellitus in young 2017-12-14 criteria provided, single submitter clinical testing The p.V244E variant (also known as c.731T>A), located in coding exon 7 of the GCK gene, results from a T to A substitution at nucleotide position 731. The valine at codon 244 is replaced by glutamic acid, an amino acid with dissimilar properties. This variant was identified in two individuals with maturity-onset diabetes of the young (Lopez AP et al. Exp. Clin. Endocrinol. Diabetes, 2009 Sep;117:391-4; Costantini S et al. Clin. Genet., 2015 May;87:440-7). 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 RCV003098539 SCV003439949 uncertain significance not provided 2022-09-13 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Val244 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22493702). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt GCK protein function. This missense change has been observed in individual(s) with GCK-related conditions (PMID: 19358091, 24735133). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 244 of the GCK protein (p.Val244Glu).

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