ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1484G>A (p.Arg495Gln) (rs794728395)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181871 SCV000234174 likely pathogenic not provided 2014-06-25 criteria provided, single submitter clinical testing p.Arg835Gln (CGG>CAG): c.2504 G>A in exon 10 of the KCNH2 gene (NM_000238.2)The R835Q variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The R835Q 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. In addition, the R835Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The R835Q residue is mostly conserved across species. Moreover, in silico analysis predicts R835Q is probably damaging to the protein structure/function. A variant at the same residue (R835W) was identified in a child with 2:1 atrioventricular block and severe ventricular arrhythmias and was not present in 200 control alleles (Lupoglazoff J et al., 2004). Nevertheless, mutations in nearby residues (T826I, D837Y, D837N, D837G, V841L) have been reported in association with LQTS, further supporting the functional importance of this region of the protein.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in LQT,ARRHYTHMIA panel(s).

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