ClinVar Miner

Submissions for variant NM_172201.1(KCNE2):c.25C>G (p.Gln9Glu) (rs16991652)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000245955 SCV000319980 benign Cardiovascular phenotype 2015-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058370 SCV000089890 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:10219239;PMID:14661677;PMID:14760488;PMID:17210839;PMID:20981092).
GeneDx RCV000170567 SCV000169913 benign not specified 2013-02-22 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000170567 SCV000919550 likely benign not specified 2018-05-08 criteria provided, single submitter clinical testing Variant summary: KCNE2 c.25C>G (p.Gln9Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 281062 control chromosomes, predominantly at a frequency of 0.017 within the African subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 243 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE2 causing Arrhythmia phenotype (7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Co-occurrences with other pathogenic variant(s) have been reported in an internal sample (KSNH2 c.1841C>T, p.A614V), providing supporting evidence for a benign role. The variant, c.25C>G, has been reported in the literature in individuals affected with SIDS (Arnestad_2007) and also in an African American patient that developed QTc prolongation, torsades de pointes (TdP), and ventricular fibrillation after administration of macrolides (Abbott_1999). Functional studies demonstrated that this variant slightly impairs channel function (Lu_2003, Perlstein_2005) and increases the potency of clarithromycin as a hERG channel blocker (Abbott_1999). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia in healthy individuals but suggest that patients with cardiomyopathies carrying this variant may develop macrolide-induced arrhythmia. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign until large scale case control studies will be available.
Invitae RCV000230885 SCV000291574 benign Long QT syndrome 6 2017-09-12 criteria provided, single submitter clinical testing
OMIM RCV000006424 SCV000026607 risk factor Long QT syndrome 6, acquired, susceptibility to 2003-12-01 no assertion criteria provided literature only

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