ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1841C>T (p.Ala614Val) (rs199472944)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000022643 SCV000263976 pathogenic Long QT syndrome 2 2015-09-10 criteria provided, single submitter clinical testing
GeneDx RCV000254785 SCV000321765 pathogenic not provided 2018-09-27 criteria provided, single submitter clinical testing The A614V variant in the KCNH2 gene has been reported in multiple individuals with LQTS and it was absent fromover 2600 control alleles, considering all publications (Tanaka et al., 1997, Nakajima et al., 1998; Sakaguchi et al.,2008; Itoh et al., 2009; Kapplinger et al., 2009; Hertz et al., 2015). This pathogenic variant was apparently de novoin one individual reported to have LQTS (Priori et al., 1999). In addition, it was shown to co-segregate with a LQTSphenotype in a least two families with multiple affected relatives (Satler et al., 1998; Tenenbaum et al., 2008). TheA614V variant was not observed in approximately 6,500 individuals of European and African American ancestry inthe NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The A614V variant is located in the intramembrane pore-forming region of KCNH2. Alanine at this position isconserved across species and in silico analysis predicts this substitution to be damaging to protein structure/function.Various functional studies demonstrate this variant to exert a dominant negative effect (Anderson et al., 2006; Itzhakiet al., 2011; Jou et al., 2013). Multiple variants in nearby residues (D609N, D609G, T613A, T613M, L615F,Y616C) have also been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al.,2014), further supporting the functional importance of this region of the protein.In summary, A614V in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae RCV000462085 SCV000543482 pathogenic Long QT syndrome 2017-11-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 614 of the KCNH2 protein (p.Ala614Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (rs199472944, ExAC no frequency). This variant has been reported in many individuals and families affected with long QT syndrome (PMID: 9024139, 9544837, 15090700, 18441445, 18808722, 19057127, 19996378, 22949429). ClinVar contains an entry for this variant (Variation ID: 29777). This variant identified in the KCNH2 gene is located in the pore region of the resulting protein (PMID: 19841300, 25348405). Experimental studies have shown that this missense change leads to a defect in KCNH2 protein trafficking and channel formation  (PMID: 16432067, 19057127, 23303164, 25417810). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000462085 SCV000740337 pathogenic Long QT syndrome 2016-08-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000462085 SCV000917558 pathogenic Long QT syndrome 2018-05-07 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.1841C>T (p.Ala614Val) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250692 control chromosomes. c.1841C>T has been reported in the literature in numerous individuals affected with Long QT Syndrome. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, such as electrophysiological findings (Itzhaki_2011) and intracellular trafficking (Anderson_2006), both of which were impaired in the presence of the variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000022643 SCV000043932 pathogenic Long QT syndrome 2 2011-03-10 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058010 SCV000089530 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:9024139;PMID:9544837;PMID:9693036;PMID:9927399;PMID:10560244;PMID:11854117;PMID:15840476;PMID:16432067;PMID:18441445;PMID:18752142;PMID:19057127;PMID:19716085;PMID:19841300;PMID:19843919;PMID:10187793). 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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