ClinVar Miner

Submissions for variant NM_000219.6(KCNE1):c.253G>A (p.Asp85Asn) (rs1805128)

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Total submissions: 20
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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 RCV000157255 SCV000050822 benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001195103 SCV000059001 risk factor Congenital long QT syndrome 2020-03-04 criteria provided, single submitter clinical testing KCNE1 c.253G>A (p.Asp85Asn) has been associated with increased risk for long QT syndrome. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Ashkenazi Jewish ancestry (2.5%, Genome Aggregation Database (gnomAD); rs1805128) and is present in ClinVar (ID: 13479). Several studies have also reported an odds ratio of 4.2-8.9 for developing Long QT syndrome in heterozygous carriers of this variant (OR=8.88 [95% CI 3.26-24.17] Kaab 2011, OR=4.21 [95% CI 1.17-15.16] Gouas 2005). In vitro functional studies provide some evidence that this variant may impact protein function (Nishio 2009). In summary, this variant is a likely risk factor for Long QT syndrome.
Blueprint Genetics RCV000157255 SCV000206985 risk factor Long QT syndrome 2015-11-30 criteria provided, single submitter clinical testing
Invitae RCV000157255 SCV000218636 benign Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247942 SCV000317782 likely benign Cardiovascular phenotype 2018-06-25 criteria provided, single submitter clinical testing in silico models in agreement (benign);Subpopulation frequency in support of benign classification
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000035353 SCV000335035 benign not specified 2015-09-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000346333 SCV000435785 likely benign Romano-Ward syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000399257 SCV000435786 likely benign Jervell and Lange-Nielsen syndrome 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000709727 SCV000435787 likely benign Long QT syndrome 5 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000057858 SCV000493202 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000035353 SCV000695996 uncertain significance not specified 2020-07-20 criteria provided, single submitter clinical testing Variant summary: KCNE1 c.253G>A (p.Asp85Asn) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0094 in 255630 control chromosomes in the gnomAD database, including 20 homozygotes. The observed variant frequency is approximately 4535 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Long QT Syndrome phenotype (2.1e-06), strongly suggesting that the variant is benign. However, multiple association studies indicate the variant is associated with LQTS (Newton-Cheh_2009, Nishio_2009, Salisbury_2006, Kolder_2015). Multiple publications have reported the variant in affected individuals, along with families that show lack of co-segregation (e.g. Nishio_2009, Maltese_2017, Nakajima_2010, Millat_2006, Lane_2018). In addition, the variant was shown to co-occur with another pathogenic/likely pathogenic variants such as SCN5A c.2946T>A, DSP c.3337C>T, KCNH2 c.98A>C KCNQ1 c.803C>T, p.Ser277Leu; KCNQ1 IVS7-2A>G, and many others in our internal database and in publications (Nishio_2009, Millat_2006, Lahtinen_2011). Independent functional studies showed that the D85N variant has a dominant-negative effect and significantly reduces tail current (Nishio_2009, Nof_2011, Lane_2018) further supporting an association with LQTS. A study based on retrospective analysis of patients provided evidence that a subset of p.Asp85Asn KCNE1-positive individuals, even in the absence of other disease-contributing variants, may manifest a mild/weak female-predominant form of LQTS that the authors denoted as "LQT5-Lite", to distinguish such potentially pro-arrhythmic common variants with incomplete penetrance (i.e. functional risk alleles) from rare pathogenic variants that truly confer monogenic disease susceptibility (Lane_2018). Multiple ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant with conflicting classifications: "risk factor" (3x), other (1x), likely benign/benign (7x), or uncertain significance (2x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000057858 SCV000747999 other not provided 2017-07-24 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709727 SCV000839964 risk factor Long QT syndrome 5 2017-06-08 criteria provided, single submitter clinical testing This c.253G>A (p.D85N) variant (rs1805128) in the KCNE1 gene is a potassium channel susceptibility allele for with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug [PMID 22100668, 24400172, 22999324, 14760488, 21244686, 17161064]. The variant has also been associated with longer QT [PMID 16132053]. A previous study has shown to predict diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5–22.9) [PMID 22100668]. This variant is considered a risk allele for drug induced long QT.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000035353 SCV000884042 benign not specified 2018-07-24 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852954 SCV000995701 benign Cardiomyopathy 2019-04-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198909 SCV001369904 uncertain significance Prolonged QT interval; Syncope; Hypertensive disorder 2018-10-15 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
OMIM RCV000014422 SCV000034671 risk factor Long QT syndrome 5, acquired, susceptibility to 2006-08-01 no assertion criteria provided literature only
OMIM RCV000014423 SCV000034672 pathogenic Long QT syndrome 2/5 2006-08-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057858 SCV000153805 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:9445165;PMID:10807545;PMID:12402336;PMID:14661677;PMID:14760488;PMID:15051636;PMID:15599693;PMID:16132053;PMID:16266404;PMID:16487223;PMID:16887036;PMID:17016049;PMID:17161064;PMID:17210839;PMID:18426444;PMID:19695459;PMID:20823649;PMID:21244686;PMID:21712262;PMID:22100668;PMID:22378279).
Medical Research Institute,Tokyo Medical and Dental University RCV000157255 SCV000222020 likely pathogenic Long QT syndrome no assertion criteria provided research

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