ClinVar Miner

Submissions for variant NM_000219.6(KCNE1):c.292C>T (p.Arg98Trp) (rs199473362)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171560 SCV000050606 uncertain significance Long QT syndrome 2018-04-05 criteria provided, single submitter research
Invitae RCV000171560 SCV000549144 likely pathogenic Long QT syndrome 2020-06-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 98 of the KCNE1 protein (p.Arg98Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs199473362, ExAC 0.01%). This variant has been reported in individuals affected with long QT syndrome or sudden unexpected death (PMID: 17341399, 16922724, 30530868, 10973849, 21070882). ClinVar contains an entry for this variant (Variation ID: 132676). This variant has been reported to affect KCNE1 protein function (PMID: 17341399, 19907016). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000619552 SCV000737536 likely pathogenic Cardiovascular phenotype 2020-01-22 criteria provided, single submitter clinical testing The p.R98W variant (also known as c.292C>T), located in coding exon 1 of the KCNE1 gene, results from a C to T substitution at nucleotide position 292. The arginine at codon 98 is replaced by tryptophan, an amino acid with dissimilar properties. In long QT syndrome cohorts, this variant has been described in patients with QT interval prolongation, repolarization abnormalities and/or syncope, aborted cardiac arrest, or sudden death upon physical exertion (Splawski I et al. Circulation. 2000;102(10):1178-85; Millat G et al. Clin Genet. 2006;70(3):214-27; Ohno S et al. Heart Rhythm. 2007;4(3):332-40; Skinner JR et al. Heart Rhythm. 2011;8(3):412-9). In one family with epilepsy and long QT syndrome, this variant did not segregate with disease and a KCNQ1 exon 2 deletion did segregate with disease (Coll M et al. PLoS ONE, 2017 Dec;12:e0189618). In studies using in vitro functional analyses, this variant adversely affected the voltage-gated potassium ion channel, resulting in decreased current amplitude, a positive shift of the voltage dependence of activation threshold, and accelerated channel deactivation (Ohno S et al. Heart Rhythm. 2007;4(3):332-40; Harmer SC et al. Am J Physiol.,Cell Physiol. 2010;298(2):C263-73). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. <br />
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709726 SCV000839963 pathogenic Long QT syndrome 5 2017-07-05 criteria provided, single submitter clinical testing This c.292C>T (p.Arg98Trp) variant in the KCNE1 gene has been reported in 6 individuals and one family from a cohort of 262 patients with long QT [PMID 10973849] and additional patients [PMID 16922724, 17341399]. Segregation of the variant with the disorder was observed in one additional family of 7 individuals, 2 of which were carrier for this variant [PMID 21070882]. Functional assays showed a modest effect of the variant on trafficking and current density [PMID 17341399]. This variant was reported in 2 heterozygous individuals from Europe and East-Asia (http://exac.broadinstitute.org/variant/21-35821641-G-A). Arginine at amino acid position 98 of the KCNE1 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 predict this p.Arg98Trp change to be deleterious. This variant thus classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001090977 SCV001246781 pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000119088 SCV000153807 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:10973849;PMID:16922724;PMID:19907016). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV001090977 SCV001790098 uncertain significance not provided 2021-06-23 no assertion criteria provided clinical testing Reported in ClinVar with conflicting interpretations of pathogenicity (ClinVar Variant ID# 132676; Landrum et al., 2016); In vitro functional studies show a reduction in potassium channel current and abnormal KCNQ1 protein trafficking (Ohno et al., 2006; Harmer et al., 2010); however additional studies are needed to validate the functional effect of this variant in vivo; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 30123799, 29766885, 29261713, 29672598, 30530868, 30461122, 31447099, 32058015, 31941373, 17341399, 16684966, 24606995, 19862833, 16945797, 16922724, 10973849, 21070882, 23861362, 24710009, 19907016)

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