ClinVar Miner

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

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000057858 SCV000884042 benign not provided 2017-07-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247942 SCV000317782 likely benign Cardiovascular phenotype 2017-06-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: in silico models in agreement (benign),Subpopulation frequency in support of benign classification
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000157255 SCV000050822 benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
Blueprint Genetics RCV000157255 SCV000206985 risk factor Long QT syndrome 2015-11-30 criteria provided, single submitter clinical testing
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).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000057858 SCV000493202 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000035353 SCV000335035 benign not specified 2015-09-21 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.
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 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000157255 SCV000435787 likely benign Long QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000057858 SCV000695996 uncertain significance not provided 2017-05-09 criteria provided, single submitter clinical testing Variant summary: The KCNE1 c.253G>A (p.Asp85Asn) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a benign outcome for this substitution. Multiple studies showed that this variant was found more frequently in LQTS patients than in controls, suggesting that it may be a risk factor for LQTS (Nishio_2009, Slisbury_2006, Kolder_2015). Independent functional studies showed that the D85N variant has a dominant-negative effect and significantly reduces tail current (Nishio_2009, Nof_2011) further supporting an association with LQTS. However, this variant was found in 1147/123924 control chromosomes (6 homozygotes) at a frequency of 0.0092557, which is approximately 4443 times the estimated maximal expected allele frequency of a pathogenic KCNE1 variant (0.0000021). Furthermore, co-occurrences of this variant and a pathogenic variant in LQTS genes have been reported (Nishio_2009, Millat_2006), suggesting this variant is possibly a benign polymorphism and not associated with the dominant Mendelian type of LQTS. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign, while others classified this variant as a risk factor for LQTS. Taken together, this variant is classified as VUS-possibly benign and a possible risk factor for LQTS.
Invitae RCV000157255 SCV000218636 benign Long QT syndrome 2018-01-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035353 SCV000059001 likely benign not specified 2017-03-20 criteria provided, single submitter clinical testing p.Asp85Asn in exon 3 of KCNE1: This variant has been identified in 2.5% (432/257 92) Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, htt p://gnomAD.broadinstitute.org; dbSNP rs1805128). It was identified in 5/208 (2.4 %) chromosomes from individuals with noise induced hearing loss and was absent i n 228 chromosomes from noise resistant individuals (Van Laer 2006). However, no data exist to support a pathogenic role in monogenic hearing loss, and the varia nt is too common in the population to be consistent with such a role. It is, the refore, classified as Likely Benign with respect to hereditary hearing loss. It should be noted that this variant was 2.8 fold enriched in a group of patients w ith long QT syndrome (LQTS) compared to healthy controls (57/2418 (2.3%) of chro mosomes from individuals with LQTS compared to 51/5856 (0.9%) of chromosomes fro m healthy controls across several studies, p=0.0001)(Paulussen 2004, Westenskow 2004, Gouas 2005, Mank-Seymour 2006, Nishio 2009, Kaab 2011). In summary, althou gh this variant is likely benign with respect to hearing loss, we cannot rule ou t a possible risk factor for long QT syndrome.
Medical Research Institute,Tokyo Medical and Dental University RCV000157255 SCV000222020 likely pathogenic Long QT syndrome no assertion criteria provided research
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000057858 SCV000747999 other not provided 2017-07-24 criteria provided, single submitter clinical testing
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

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