Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002271379 | SCV000052535 | uncertain significance | not specified | 2022-06-14 | criteria provided, single submitter | clinical testing | Variant summary: GCK c.440G>A (p.Gly147Asp) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251454 control chromosomes. c.440G>A has been reported in the literature in at-least two individuals from a single family affected with features of Maturity-onset diabetes of the young (MODY) (example, Katashima_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Broad Center for Mendelian Genomics, |
RCV001248972 | SCV001422804 | uncertain significance | Monogenic diabetes | 2020-01-22 | criteria provided, single submitter | curation | The p.Gly147Asp variant in GCK has been reported in 1 individual with Monogenic Diabetes in ClinVar (Variation ID: 36217), and has been identified in 0.002892% (1/34580) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922296). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar and as a VUS in the literature (Variation ID: 36217; PMID: 27080136). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in GCK in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP2, PP3 (Richards 2015). |
| Invitae | RCV003565386 | SCV004319711 | uncertain significance | not provided | 2023-10-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 147 of the GCK protein (p.Gly147Asp). This variant is present in population databases (rs193922296, gnomAD 0.003%). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 34746319; Invitae). ClinVar contains an entry for this variant (Variation ID: 36217). 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. 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. |