ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.675C>G (p.Ile225Met)

dbSNP: rs772754004
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657901 SCV000779666 pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing The I225M missense variant in the GCK gene has been reported previously in association with MODY (Massa et al., 2001; Beer et al., 2012). Functional studies report that I225M demonstrates an inactivating effect on enzyme activity (Beer et al., 2012). The variant is not observed in large population cohorts (Lek et al., 2016). The variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (G223S/R/V, M224R/T, V226M/L/E, G227R/S/C) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this to be a pathogenic variant.
Ambry Genetics RCV003343982 SCV004057900 uncertain significance Maturity onset diabetes mellitus in young 2023-08-21 criteria provided, single submitter clinical testing The p.I225M variant (also known as c.675C>G), located in coding exon 6 of the GCK gene, results from a C to G substitution at nucleotide position 675. The isoleucine at codon 225 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in several individuals with diabetes or clinical suspicion of maturity-onset diabetes of the young (Massa O et al. Diabetologia, 2001 Jul;44:898-905; Mirshahi UL et al. Am J Hum Genet, 2022 Nov;109:2018-2028; Marucci A et al. Acta Diabetol, 2023 Jan;60:131-135). In one individual with a history of hyperglycemia, negative autoantibodies, and a parent with diabetes, this variant was identified in cis with a second GCK missense varaint. (Beer NL et al. Diabetes Care, 2012 Jul;35:1482-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000657901 SCV004295166 uncertain significance not provided 2024-01-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 225 of the GCK protein (p.Ile225Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (PMID: 11508276, 22611063, 36227502). ClinVar contains an entry for this variant (Variation ID: 546098). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GCK protein function. Experimental studies have shown that this missense change affects GCK function (PMID: 22611063). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

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