ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1973A>G (p.Asn658Ser) (rs1057523338)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000426599 SCV000531592 likely pathogenic not provided 2016-12-20 criteria provided, single submitter clinical testing The N658S likely pathogenic in the KCNH2 gene has not been published as a pathogenic or benign variant to our knowledge. The N658S 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. Although the N658S variant is a conservative amino acid substitution, which may not impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the N658S variant.
Invitae RCV000466780 SCV000543474 uncertain significance Long QT syndrome 2016-08-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 658 of the KCNH2 protein (p.Asn658Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNH2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant identified in the KCNH2 gene is located in the transmembrane S6 region of the resulting protein (PMID: 19841300, 25348405), but it is unclear how this variant impacts the function of this protein. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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