ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.128G>A (p.Arg43His) (rs764232985)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Translational Genomics Laboratory,University of Maryland School of Medicine RCV000445457 SCV000537123 likely pathogenic Monogenic diabetes 2016-07-22 criteria provided, single submitter clinical testing The c.128G>A variant in codon 43 (exon 2) of the glucokinase gene, GCK, results in the substitution of Arginine to Histidine. This variant has been reported in the literature in patients with a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (22611063, 22493702, 11942313), with evidence of co-segregation with diabetes in two separate families (22611063, 22493702). Different amino acid substitutions at this residue, Arg43Ser and Arg43Cys, have also been reported in patients with MODY2 (17573900, 19358091, 25015100). Functional studies suggest that the Arg43His and Arg43Cys substitutions result proteins with decreased stability compared to wild-type (22611063, 25015100). Additionally, multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, LRT, FATHMM, SVM, LR, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS3, PP1, PP3
Athena Diagnostics Inc RCV000711763 SCV000842157 likely pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000445457 SCV001422799 likely pathogenic Monogenic diabetes 2020-01-22 no assertion criteria provided curation The p.Arg43His variant in GCK has been reported in at least 8 individuals (including 1 German, 1 Slovakian, 1 Swiss, 1 Cyproit, and 1 Hispanic individuals) with Monogenic Diabetes, segregated with disease in 6 affected relatives from 2 family (PMID: 11942313, 24430320, 11942313, 22611063, 22493702, 27106716; DOI:10.3252/pso.eu.54espe.2015; Shammas et al. 2012), and has been identified in 0.002891% (1/34592) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764232985). 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 (Variation ID: 393453). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg43Cys, has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 21348868, 30592380, 21521320, 23771172, 19790256, 25015100/Variation ID: 585911). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate, PM5, PM2_Supporting, PP3, PP1_moderate (Richards 2015).

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