ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.703A>G (p.Met235Val) (rs1057521093)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000419860 SCV000521046 likely pathogenic not provided 2016-08-02 criteria provided, single submitter clinical testing The M235V variant has been published previously in association with MODY (García-Herrero et al., 2007). It 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. M235V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and functional studies have shown M235V results in lowered protein stability at higher temperatures as well as lowered catalytic activity compared to wild type (García-Herrero et al., 2007). Missense variants in the same codon (M235T/R) and in nearby residues (A232D, C233R/S, Y234H, E236K/A, E237K) 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.

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