ClinVar Miner

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

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Total submissions: 22
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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 2020-12-07 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 RCV001195103 SCV000435785 likely benign Congenital long QT 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 RCV001282926 SCV000884042 benign none provided 2020-03-20 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 RCV000399257 SCV001369904 uncertain significance Jervell and Lange-Nielsen syndrome 2 2018-10-15 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PP5,BS1,BP6.
GeneDx RCV000057858 SCV001899783 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19019189, 32429735, 31447099, 31918855, 30384889, 17266934, 29874177, 28798025, 28003625, 29625280, 29540472, 27509294, 14760488, 24400172, 24561134, 19695459, 22999324, 20823649, 25119684, 16823764, 23237912, 23631430, 22995991, 21712262, 16132053, 22378279, 15051636, 22100668, 21244686, 17161064)
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000057858 SCV001553666 likely benign not provided no assertion criteria provided clinical testing The KCNE1 p.D85N variant was identified in 93 of 4968 proband chromosomes (frequency: 0.0187) from individuals or families with Long QT syndrome (LQTS), however many of these individuals carried variants in other LQTS-related genes (Nishio_2009_PMID:19695459; Lahtinen_2011_PMID:21244686; Kaab_2012_PMID:22100668; Hasegawa_2014, Lane_2018_PMID:29625280). A 10 year old boy with LQTS was found to carry the KCNE1 p.D85N variant along with two other variants: KCNH2 p.N45D and SCN5A p.A1428S, 4282G>T; the proband's unaffected mother and unaffected aunt also carried the KCNE1 p.D85N variant (Yoshikane_2013_PMID:23237912). Another family was reported in which the LQTS-affected proband and daughter carried the KCNE1 p.D85N and KCNH2 p.E58K variants; the proband's unaffected eldest son carried the KCNH2 p.E58K variant and the unaffected youngest son carried the KCNE1 p.D85N variant (Hasegawa_2014). These findings suggest that the p.D85N variant may contribute to or modify disease but likely is not causal. Functional studies demonstrated that the KCNE1 p.D85N variant modified KCNQ1/KCNE1 currents, however this was attenuated when tested in conjunction with another LQTS-associated variant (Hasegawa_2014, Nishio_2009_PMID:19695459). The variant was identified in dbSNP (ID: rs1805128) and ClinVar (classified as benign by Invitae, EGL Genetics and three other laboratories, as likely benign by Laboratory for Molecular Medicine, Ambry Genetics and Illumina, as uncertain significance by Integrated Genetics and CeGaT Praxis fuer Humangenetik Tuebingen, as risk factor by Blueprint Genetics and Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine and as likely pathogenic by Medical Research Institute, Tokyo Medical and Dental University). The variant was identified in control databases in 2637 of 282814 chromosomes (22 homozygous) at a frequency of 0.009324 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 263 of 10368 chromosomes (freq: 0.02537), European (Finnish) in 424 of 25120 chromosomes (freq: 0.01688), European (non-Finnish) in 1580 of 129142 chromosomes (freq: 0.01223), Other in 65 of 7228 chromosomes (freq: 0.008993), East Asian in 111 of 19946 chromosomes (freq: 0.005565), Latino in 97 of 35438 chromosomes (freq: 0.002737), African in 54 of 24956 chromosomes (freq: 0.002164), and South Asian in 43 of 30616 chromosomes (freq: 0.001404). The p.D85 residue is conserved in mammals however four of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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