ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.676G>A (p.Val226Met) (rs148311934)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029906 SCV000052561 pathogenic Maturity-onset diabetes of the young, type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
GeneDx RCV000255932 SCV000322348 pathogenic not provided 2018-09-13 criteria provided, single submitter clinical testing The V226M missense variant in the GCK gene has been reported previously in association with MODY (Velho et al., 1997; Pruhova et al., 2010; Vits et al., 2006). This variant has been shown to segregate with disease in many affected individuals from several families in published literature (Henderson et al., 2007) or referred for genetic testing at GeneDx. The V226M variant is observed in 2/111,690 (0.0018%) alleles from individuals of non-Finnish European background in the gnomAD dataset (Lek et al., 2016). This substitution occurs at a position in the hexokinase subdomain that is conserved across species, and functional studies have shown that V226M leads to decreased enzyme activity of the glucokinase protein (Davis et al., 1999). However, another functional study theorized V226M may lead to a milder phenotype in comparison to other GCK pathogenic variants, as it leads to increased stability of the glucokinase protein while simltaneously decreasing its activity (Raimondo et al., 2014). Missense variants in the same codon (V226L/E) have been reported in association with MODY (Borowiec et al., 2012; Pruhova et al., 2010), as have missense variants in nearby residues (M224R/T, I225F/M, G227R/S/C, T228A/M/R/K) in the Human Gene Mutation Database (Stenson et al., 2014), supporting the functional importance of this region of the protein. The V226M variant is reported as pathogenic in ClinVar but additional evidence is not available (Landrum et al., 2016; SCV000594954.1). We interpret V226M as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000029906 SCV000594954 pathogenic Maturity-onset diabetes of the young, type 2 2016-07-19 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000255932 SCV000613449 pathogenic not provided 2020-09-24 criteria provided, single submitter clinical testing This is reported to be a founder variant in the Quebec region of Canada (PMID: 17079173), and is statistically more frequent in affected individuals than in the general population and/or healthy controls ( Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant resulted in reduced ATP affinity and catalytic activity that could be due to increased protein instability (PMID: 10426385, 10525657, 25015100). This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Computational tools predict that this variant is damaging.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000029906 SCV000891242 likely pathogenic Maturity-onset diabetes of the young, type 2 2016-10-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763584 SCV000894423 pathogenic Permanent neonatal diabetes mellitus; Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young, type 2 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825615 SCV000966967 pathogenic Maturity onset diabetes mellitus in young 2018-09-25 criteria provided, single submitter clinical testing The p.Val225Met variant in GCK has been reported in >15 individuals with maturit y-onset diabetes of the young (MODY) and segregated with disease in at least 8 a ffected members across 6 families (Velho 1997, Pruhova 2003, Henderson 2007, Del vecchio 2014, Alkorta-Aranburu 2014, Raimondo 2014, Bennett 2015; note that most studies report this variant as p.Val226Met). This variant has also been identif ied in 0.002% (2/111690) of European chromosomes by gnomAD (http://gnomad.broadi In vitro functional studies support an impact to protein function (Davis 1999, Miller 1999, Raimondo 2014). Furthermore, multiple amino acid chan ges at the same position (p.Val225Glu, p.Val225Leu) have been reported in indivi duals with MODY, suggesting that changes to this position may not be tolerated. Finally, this variant as been reported as Pathogenic in ClinVar (Variation ID 36 243). In summary, the p.Val225Met variant meets criteria to be classified as pat hogenic for autosomal dominant MODY based on case observations, segregation stud ies, low frequency in controls, and functional evidence. ACMG/AMP criteria appli ed: PS4, PP1_Strong, PM2_Supporting, PS3_Supporting.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV000825615 SCV001656170 pathogenic Maturity onset diabetes mellitus in young 2017-12-12 criteria provided, single submitter clinical testing The c.676G>A (p.Val226Met, rs148311934) variant in exon 6 of GCK is a known pathogenic variant that has been reported in the medical literature (PMID: 17079173). This G to A transition results in the substitution of valine to methionine at amino acid position 226, which results in reduced enzymatic activity of glucokinase (PMID: 25015100).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.