ClinVar Miner

Submissions for variant NM_000238.3(KCNH2):c.1682C>T (p.Ala561Val) (rs121912504)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620827 SCV000737720 pathogenic Cardiovascular phenotype 2016-09-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057941 SCV000089461 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:7889573;PMID:9927399;PMID:10973849;PMID:11113008;PMID:11468227;PMID:11668638;PMID:11854117;PMID:15051636;PMID:15840476;PMID:16432067;PMID:17160940;PMID:17445409;PMID:18441445;PMID:18593567;PMID:19716085;PMID:19841300;PMID:9024139). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626630 SCV000747331 likely pathogenic Obesity; Prolonged QT interval 2017-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000181806 SCV000234109 pathogenic not provided 2018-09-11 criteria provided, single submitter clinical testing The A561V pathogenic variant in the KCNH2 gene has been reported many times in association with LQTS (Curran et al., 1995; Priori et al., 1999; Splawski et al., 2000; Larsen et al., 2001; Moss et al., 2002; Tester et al., 2005; Hsueh et al., 2008; Kapplinger et al., 2009; Horigome et al., 2010; Giudicesi et al., 2012; Abrams et al., 2014; Christiansen et al., 2014; Riuro et al., 2014; Ozawa et al., 2016) and has been observed in multiple other unrelated individuals referred for LQTS genetic testing at GeneDx. Furthermore, in vitro functional studies suggests a dominant negative effect of A561V leads to ion channel suppression (Kagan et al., 2000; Anderson et al., 2006; Li et al., 2007). Although A561V is a conservative amino acid substitution, this residue is located in a pore region of the KCNH2 gene where pathogenic variants have been linked to a greater risk for arrhythmia-related cardiac events (Moss et al., 2002; Nagaoka et al., 2008). In addition, other missense variants involving the same residue (A561T, A561P) have been reported in association with LQTS, further supporting the functional importance of this residue (Stenson et al., 2014). Moreover, the A561V variant is not observed in large population cohorts (Lek et al., 2016). In summary, A561V in the KCNH2 gene is interpreted as a pathogenic variant.
Invitae RCV000229360 SCV000283966 pathogenic Long QT syndrome 2017-06-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 561 of the KCNH2 protein (p.Ala561Val). 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 (ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome, and has been shown to cosegregate with disease in affected families (PMID: 22949429, 7889573, 18593567, 24606995, 24606995, 10973849). ClinVar contains an entry for this variant (Variation ID: 14420). Several functional studies have shown that this variant has a deleterious effect on the expression and localization of the KCNH2 protein which is part of the potassium channel (PMID: 16432067, 17445409, 23303164, 12354768, 24623279). A different missense substitution at this codon (p.Ala561Thr) is reported to be deleterious (PMID: 23303164, 10973849). This indicates that the alanine residue is important for KCNH2 protein function. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015501 SCV000035766 pathogenic Long QT syndrome 2 2000-04-14 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000181806 SCV000924810 pathogenic not provided 2016-04-08 no assertion criteria provided provider interpretation

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