ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.1135T>C (p.Trp379Arg) (rs199472768)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057559 SCV000089078 not provided SUDDEN INFANT DEATH SYNDROME no assertion provided literature only This variant has been reported as associated with Sudden infant death syndrome in the following publications (PMID:17222736;PMID:22677073). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000505766 SCV000234482 likely pathogenic not provided 2017-04-24 criteria provided, single submitter clinical testing A variant that is likely pathogenic was identified in the KCNQ1 gene. The W379R variant has been published previously in association with LQTS (Vyas et al., 2006; Tester et al., 2007). This variant was initially was reported in a 48 year-old female patient with a QTc of 483 ms, who had a daughter with recurrent syncope and positive stress test who also harbored W379R, as well as a 17 year old daughter who died suddenly (Vyas et al., 2006). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W379R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, functional studies demonstrated that this variant results in a loss of function of the ion channel compared to wild type channels (Steffensen et al., 2015). However, while missense variants in the same residue (W379S, W379G) and in nearby residues (L374H, R380G, R380S) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined.
Invitae RCV000462343 SCV000543319 uncertain significance Long QT syndrome 2016-05-20 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 379 of the KCNQ1 protein (p.Trp379Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (rs199472768, ExAC no frequency). This variant has been reported in two related individuals affected with long QT syndrome (PMID: 26066609) and has also been observed in two cases of unexplained sudden death (PMID: 17222736, 22677073). ClinVar contains an entry for this variant (Variation ID: 67013). Experimental studies have shown that this missense change has a deleterious effect on KCNQ1 activity (PMID: 26066609). In summary, this variant is a rare missense change with a deleterious effect on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000462343 SCV000747934 pathogenic Long QT syndrome 2016-05-31 criteria provided, single submitter clinical testing

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