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

gnomAD frequency: 0.00841  dbSNP: rs1805128

Total submissions: 23

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, Mass General Brigham 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	likely benign	Long QT syndrome	2022-11-01	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000035353	SCV000335035	benign	not specified	2015-09-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001195103	SCV000435785	likely benign	Congenital long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, 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 Center for Human Genetics Tuebingen	RCV000057858	SCV000493202	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	KCNE1: BS1, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035353	SCV000695996	likely benign	not specified	2023-09-25	criteria provided, single submitter	clinical testing
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	RCV000057858	SCV000884042	benign	not provided	2023-11-29	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)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224097	SCV003920090	uncertain significance	Jervell and Lange-Nielsen syndrome 2; Long QT syndrome 5	2021-03-30	criteria provided, single submitter	clinical testing	KCNE1 NM_000219.4 exon 4 p.Asp85Asn (c.253G>A): This variant has been reported in the literature in several individuals with LQTS and is reported to be overrepresented in this patient population compared to control individuals (Westenskow 2004 PMID:15051636, Nishio 2009 PMID:19695459, Kaab 2012 PMID:22100668, Weeke 2014 PMID:24561134, Maltese 2017 PMID:28003625, Lane 2018 PMID:29625280). Several authors in the literature suggest that this variant may act as a risk allele or modifying allele (Gouas 2005 PMID:16132053, Lahtinen 2011 PMID:21244686, Weeke 2014 PMID:24561134, Lane 2018 PMID:29625280). However, this variant is also present in 2.5% (263/10368) of Ashkenazi Jewish alleles in the Genome Aggregation Database, including 5 homozygotes (https://gnomad.broadinstitute.org/variant/21-35821680-C-T), suggesting that it may be a benign polymorphism. This variant is present in ClinVar (Variation ID:13479). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies do predict that this variant will impact the protein (Gouas 2005 PMID:16132053, Nishio 2009 PMID:19695459, Nof 2011 PMID:21712262, Du 2013 PMID:24400172). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
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, digenic	2006-08-01	flagged submission	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		flagged submission	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.