ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1516C>T (p.Pro506Ser) (rs199473006)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181874 SCV000234177 likely pathogenic not provided 2017-04-28 criteria provided, single submitter clinical testing The P846S variant in the KCNH2 gene has been reported previously in one individual with LQTS and was absent from 2,600 control alleles (Kapplinger J et al., 2009). A different amino acid change at the same codon (P846T) has also been reported previously in association with LQTS (Nagaoka I et al., 2008; Itoh H et al., 2010). Functional studies demonstrated P846T leads to a significant decrease in current density and results in a loss of function effect on the ion channel (Oka Y et al., 2010). P846S results in a non-conservative amino acid substitution of a non-polar Proline with a polar Serine at a residue that is conserved across species. Furthermore, the the P846S variant was not observed with any significant frequency 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.Therefore, this variant is likely pathogenic
Invitae RCV000464496 SCV000543431 uncertain significance Long QT syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 846 of the KCNH2 protein (p.Pro846Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency) . This variant has been reported in an individuals referred for long QT syndrome testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67409). This variant identified in the KCNH2 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). Experimental studies have shown that this missense change causes a defect in protein trafficking (PMID: 25417810). In summary, this is a rare variant which has been shown to affect protein function. However, the current clinical and genetic evidence is not sufficient to establish pathogenicity. Therefore, this variant has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058133 SCV000089653 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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