ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.878T>C (p.Ile293Thr)

dbSNP: rs2128820046
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001756594 SCV001986066 uncertain significance not provided 2020-01-09 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23155715)
Geisinger Clinic, Geisinger Health System RCV002285492 SCV002562198 likely pathogenic Maturity-onset diabetes of the young type 2 2022-08-02 criteria provided, single submitter research PM2, PP3, PP1, PS4_Moderate, PM5, PP4, PP2
Genetics and Molecular Pathology, SA Pathology RCV002285492 SCV004175274 uncertain significance Maturity-onset diabetes of the young type 2 2023-07-25 criteria provided, single submitter clinical testing The GCK c.878T>C variant is classified as a VUS (PM2_Supporting, PP2, PP3, PP4) The GCK c.878T>C variant is a single nucleotide change in exon 8/10 of the GCK gene, which is predicted to change the amino acid isoleucine at position 293 in the protein to threonine. This variant is absent from population databases (PM2_Supporting). It has been reported in the literature in 3 unrelated individuals presenting with MODY (PMID: 36257325, 23155715). It is a missense variant in a constrained gene where missense variants are a common mechanism of disease and benign variation is rare (PP2). Computational predictions support a deleterious effect on the gene or gene product (PP3). This is a novel missense change at an amino residue where a different likely pathogenic missense change has been seen before (p.Ile293Arg, PMID: 34789499, 36257325). The clinical features of this case are highly specific for the GCK gene and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). The variant has been reported in the HGMD database as disease causing (CM1211061) and has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 1303095). It has not been reported in dbSNP.

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