ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1448G>A (p.Arg483Gln) (rs1064793147)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481087 SCV000565058 likely pathogenic not provided 2015-03-02 criteria provided, single submitter clinical testing A novel R823Q variant that is likely pathogenic was identified in the KCNH2 (HERG) gene. The R823Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The R823Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the cyclic nucelotide binding domain that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same residue (R823W) and in nearby residues (G820R, G820E, V822M, T826I) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this region of the protein. In the same in vitro system as above, R823W was shown to abolish potassium current in cells expressing this mutant channel, suggesting that the R823Q variant may have a more mild phenotypic effect (Cui et al., 2001). Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.

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