ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000255932 SCV000613449 pathogenic not provided 2017-04-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763584 SCV000894423 pathogenic Permanent neonatal diabetes mellitus; Diabetes mellitus type 2; Hyperinsulinemic hypoglycemia familial 3; Maturity-onset diabetes of the young, type 2 2018-10-31 criteria provided, single submitter clinical testing
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
Integrated Genetics/Laboratory Corporation of America RCV000029906 SCV000052561 pathogenic Maturity-onset diabetes of the young, type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
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 nstitute.org). 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.
Molecular Diagnostics Laboratory,M Health: University of Minnesota RCV000029906 SCV000891242 likely pathogenic Maturity-onset diabetes of the young, type 2 2016-10-04 criteria provided, single submitter clinical testing

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