ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.106C>T (p.Arg36Trp) (rs762263694)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497478 SCV000589597 likely pathogenic not provided 2017-06-21 criteria provided, single submitter clinical testing The R36W variant has been previously published many times in association with GCK-MODY (see Hager et al., 1994; Vits et al., 2006; Stanik et al., 2012). The R36W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R36W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and nearby residues (R36Q, V33A, M37R, Q38P, E40K) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Genetic Services Laboratory,University of Chicago RCV000503648 SCV000594957 pathogenic Maturity-onset diabetes of the young, type 2 2017-02-16 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000497478 SCV000613394 pathogenic not provided 2017-02-02 criteria provided, single submitter clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV000788107 SCV000925754 pathogenic Maturity onset diabetes mellitus in young 2018-07-20 criteria provided, single submitter clinical testing The c.106C>T variant (rs762263694) is located in exon 2 of the GCK gene. The C to T transition results in the substitution of arginine for tryptophan at amino acid position 36 of the glucokinase protein. This same variant, as well as a different missense change involving the same amino acid residue (p.Arg36Gln), has been reported in the heterozygous state in several individuals with MODY (PMIDs: 8168652, 25555642, 24097065, 22540858 and others). This is a rare variant in the general population (GnomAD), and the substitution occurs at a position that is highly conserved across species.

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