Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000711767 | SCV000842161 | uncertain significance | not provided | 2018-03-01 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000711767 | SCV001155071 | likely pathogenic | not provided | 2019-04-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000711767 | SCV002129033 | uncertain significance | not provided | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 455 of the GCK protein (p.Val455Glu). This variant is present in population databases (rs753795627, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical history consistent with GCK-related conditions (PMID: 19002431, 25555642, 31264968, 34789499, 36400171; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 585916). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCK function (PMID: 18481947). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002469275 | SCV002765941 | likely pathogenic | Maturity-onset diabetes of the young type 2 | 2022-11-27 | criteria provided, single submitter | clinical testing | Variant summary: GCK c.1364T>A (p.Val455Glu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 238652 control chromosomes. c.1364T>A has been reported in the literature in individuals affected with features of Maturity Onset Diabetes Of The Young 2 (e.g. Lukasova_2008, Gloyn_2009, Colclough_2022). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function suggesting that the variant has an inactivating effect on the protein and reduces activity (e.g. Gloyn_2008, Langer_2021). The most pronounced variant effect results in 10%-<30% of normal activity (Gloyn_2008) consistent with the established molecular mechanism of disease. Four ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments, with two citing the variant as uncertain significance, one citing the variant as likely pathogenic, and one citing the variant as pathogenic. Some submitters cite overlapping, but not all inclusive evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Gene |
RCV000711767 | SCV003927524 | likely pathogenic | not provided | 2023-05-25 | criteria provided, single submitter | clinical testing | Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18271687, 18481947, 31264968, 36400171, 36208030, 34789499, 19002431, 34662886, 34532767) |
| Laboratory of Diagnostic Genome Analysis, |
RCV000711767 | SCV002035523 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000711767 | SCV002037348 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Seattle Children's Hospital Molecular Genetics Laboratory, |
RCV003446380 | SCV004174098 | pathogenic | Maturity-onset diabetes of the young type 1 | no assertion criteria provided | clinical testing |